AU2006251154A1 - 17beta-HSD1 and STS inhibitors - Google Patents

Description

WO 2006/125800 PCT/EP2006/062587 1 17p-HSDI AND STS INHIBITORS 5 Description FIELD OF INVENTION 10 The present invention relates to novel substituted steroid derivatives which represent selec tive inhibitory compounds of the 17p-hydroxysteroid dehydrogenase type I (17p-HSD1) enzyme, and, in addition, which may represent inhibitors of the steroid sulphatase, as well as to the salts of these compounds, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use 15 of said novel substituted steroid derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of the 17p-HSD1 enzyme and/or steroid sulphatase enzymes and/or requiring the lowering of the endogenous 17p-estradiol concentration. 20 BACKGROUND The publications and other materials used herein to illuminate the background of the inven tion, and in particular, cases to provide additional details respecting the practice, are incorporated by reference. 25 Mammalian 17p-hydroxysteroid dehydrogenases (17p-HSDs) are NAD(H) or NADP(H) de pendent enzymes which convert inactive 17-keto-steroids into their active 17p-hydroxy-forms or catalyse the oxidation of the 17p-hydroxy-forms into the 17-keto-steroids. Because both estrogens and androgens have the highest affinity for their receptors in the 17p-hydroxy form, 17p-HSD en 30 zymes play an essential role in the tissue-selective regulation of the activity of sex steroid hor mones. At present, 10 human members of the 17P-HSD enzyme family have been described (types 1-5, 7, 8, 10-12)., whereby each type of 17P-HSD has a selective substrate affinity, direc tional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. 35 Due to their essential role in the tissue-selective regulation of the activity of sex steroid hor mones, 17p-HSDs can be involved in the occurrence and development of estrogen-sensitive pa thologies (f. ex. breast, ovarian, and endometrium cancers etc.) and androgen-sensitive patholo gies (f. ex. prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Furthermore, many WO 2006/125800 PCT/EP2006/062587 2 types of 17-HSD have been shown to be involved in the pathogenesis of particular human disor ders such as pseudohermaphroditism (17p-HSD3), polycystic kidney disease (17p-HSD8) and bi functional enzyme deficiency (17p-HSD4) [reviewed by: Mindnich et al (2004)]. Therefore treatment of sex steroid-sensitive diseases by administration of specific inhibitors of the 17p-HSDs enzymes 5 have been suggested, optionally in combination with potent and specific anti-estrogens and anti androgens [Labrie et al. (1997)]. The best characterized member of the 17p-HSD family is the 173-HSD1 [EC 1.1.1.62]. The 17p-HSD1 enzyme catalyzes in vitro the reduction and the oxidation between estrone (El) and es 10 tradiol (E2). However, under physiological in vivo conditions the enzyme only catalyses the reduc tive reaction from the estrone (El) to the estradiol (E2). The 17p-HSD1 was found to be expressed in a variety of hormone-dependent tissues, e.g. placenta, mammary gland tissue or uterus and en dometrium tissue, respectively. 15 Estradiol itself is, especially in comparison to the significantly less active estrone, a very po tent hormone, which regulates the expression of a variety of genes by binding to the nuclear estro gen receptor and plays an essential role in the proliferation and differentiation of the target cell. Physiological as well as pathological cell proliferations can be estradiol dependent. Especially many breast cancer cells are stimulated by a locally raised estradiol concentration. Furthermore, 20 the occurrence or course of benign pathologies such as endometriosis, uterine leiomyomas (fi broids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhoea is dependent from the existence of significantly high estradiol levels. Endometriosis is a well-known gynaecological disorder that affects 10 to 15% of women in 25 the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde men struation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lin ing, and are then able to implant and grow. The implants respond to steroid hormones of the men 30 strual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tis sue. The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the le sions. Some women with severe endometriosis are asymptomatic, while women with mild endome 35 triosis may have severe pain. Up to now, no reliable non-invasive test is available to diagnose en dometriosis. Laparoscopy has to be performed to diagnose the disease. Endometriosis is classified according to the 4 stages set up by the American Fertility Society (AFS). Stage I corresponds to minimal disease while stage IV is severe, depending on the location and the extent of the endome- WO 2006/125800 PCT/EP2006/062587 3 triosis. Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe en dometriosis can cause tubal damage and adhesions leading to infertility. The aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if de 5 sired). The two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof. Uterine leiomyomas (fibroids or myomas), benign clonal tumours, arise from smooth muscle cells of the human uterus. They are clinically apparent in up to 25% of women and are the single, 10 most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, re productive dysfunction. Myomas are found submucosally (beneath the endometrium), intramurally (within the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types. The presence of estrogen receptors in leio 15 myoma cells has been studied by Tamaya et al. [Tamaya et al. (1985)]. They have shown that the ratios of estrogen receptor compared to progesterone and androgen receptor levels were higher in leiomyomas than in the corresponding normal myometrium. Surgery has long been the main treat ment for myomas. Furthermore, medical therapies that have been proposed to treat myomas in clude administration of a variety of steroids such as the androgenic steroids danazol or gestrinone 20 and progestogens, or of compounds modulating the steroid hormone plasma levels like e.g. GnRH agonists and GnRH antagonists, whereby the administration is often associated a variety of serious side-effects. Everything that has been said above in relation to the treatment of uterine leiomyomas and 25 endometriosis equally applies to other benign gynaecological disorders, notably adenomyosis, functional menorrhagia and metrorrhagia. These benign gynaecological disorders are all estrogen sensitive and are treated in a comparable way as described herein before in relation to uterine leiomyomas and endometriosis. The available pharmaceutical treatments, however, suffer from the same major drawbacks, i.e. they have to be discontinued once the side-effects become more seri 30 ous than the symptoms to be treated and symptoms reappear after discontinuation of the therapy. Since the aforementioned malign and benign pathologies are all 17p-estradiol dependent, a reduction of the endogenous 17p-estradiol concentration in the respective tissue will result in an impaired or reduced proliferation of 17p-estradiol responsive cells in said tissues. Therefore, selec 35 tive inhibitors of the 17P-HSD1 enzyme are well suited for their use to impair endogenous produc tions of estrogens, in particular of 17p-estradiol, in myomas, endometriotic, adenomyotic and en dometrial tissue. The application of a compound acting as selective inhibitor on the 17p-HSD1 which preferentially catalyses the reductive reaction will result in a lowered intracellular estradiol- WO 2006/125800 PCT/EP2006/062587 4 concentration, since the reductive conversion of the estrone into the active estradiol is reduced or suppressed. Therefore, reversible or even irreversible inhibitors of the 17p-HSD1 may play a sig nificant role in the prophylaxis and/or treatment of steroid-hormone, in particular 17p-estradiol, de pendent disorders or diseases. Furthermore, the reversible or even irreversible inhibitors of the 5 17-HSD1 should have no or only pure antagonistic binding activities to the estradiol receptor, in particular to the estrogen receptor a subtype, since agonistic binding of the estrogen receptor would lead to activation and subsequently to the proliferation and differentiation of the target cell. In contrast, antagonists of the estrogen receptor, so called anti-estrogens, bind competitively to the specific receptor protein thus preventing access of endogenous estrogens to their specific binding 10 site. At present it is described in the literature that several malignant disease as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperpla sia may be treated by the administration of a selective 17p-HSD1 inhibitor. Furthermore, a selective 15 17-HSD1 inhibitor may be useful for the prevention of the aforementioned hormone-dependent cancers, especially breast cancer (e.g. WO 2004/080271). Furthermore, international patent appli cation WO 03/017973 describes the use of a selective estrogen enzyme modulator (SEEM) in the manufacture of a drug delivery vehicle for intravaginal administration to treat or prevent a benign gynaecological disorder such as endometriosis in a mammalian female. 20 Another known target for estrogen deprivation is the steroid sulphatase enzyme (STS) (E.C. 3.1.6.2), which regulates the local production of estrogens and androgens from systemic precur sors in several tissues [reviewed by Reed et al (2005)]. The enzyme catalyzes the hydrolysis of the sulphate esters of 3-hydroxy steroids, which are inactive transport or precursor forms of the active 25 3-hydroxy steroids. In particular, STS hydrolyzes in-active estron-sulphate into estrone, which is then further converted into the active estradiol by action of the above described 17p-HSD1 en zyme. Therefore, STS has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body and its action is implicated in physiological processes and pathological conditions, such as hormone-dependent tumors. STS expression is in 30 creased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth of the breast and prostate prompted the development of potent STS inhibitors, since STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones. Therefore, they are considered as potential therapeutic agents for the treatment of estrogen- and androgen-dependent disorders in general. Indications may range from cancers of 35 the breast, endometrium and prostate to disorders of the pilosebaceous unit, e. g. acne, androge netic alopecia, and hirsutism. Furthermore, STS inhibitors may be useful as immunosuppressive agents, and have been shown to enhance memory when delivered to the brain.

WO 2006/125800 PCT/EP2006/062587 5 Acne is a polyetiological disease caused by the interplay of numerous factors, such as in heritance, sebum, hormones, and bacteria. The most important causative factor in acne is sebum production; in almost all acne patients sebaceous glands are larger and more sebum is produced than in persons with healthy skin. The development of the sebaceous gland and the extent of se 5 bum production is controlled hormonally by androgens; therefore, androgens play a crucial role in the pathogenesis of acne. In man, there are two major sources supplying androgens to target tis sues: (i) the gonades which secrete testosterone, (ii) the adrenals producing dehydroepiandroster one (DHEA) which is secreted as the sulfate conjugate (DHEAS). Testosterone and DHEAS are both converted to the most active androgen, dihydrotestosterone (DHT), in the target tissue, e. g. in 10 the skin. There is evidence that these pathways of local synthesis of DHT in the skin are more im portant than direct supply with active androgens from the circulation. Therefore, reduction of en dogeneous levels of androgens in the target tissue by specific inhibitors should be of therapeutic benefit in acne and seborrhoea. Furthermore, it opens the perspective to treat these disorders through modulation of local androgen levels by topical treatment, rather than influencing circulating 15 hormone levels by systemic therapies. Androgenetic male alopecia is very common in the white races, accounting for about 95% of all types of alopecia. Male-pattern baldness is caused by an increased number of hair follicles in the scalp entering the telogen phase and by the telogen phase lasting longer. It is a genetically de 20 termined hair loss affected through androgens. Elevated serum DHEA but normal testosterone lev els have been reported in balding men compared with non-balding controls, implying that target tis sue androgen production is important in androgenetic alopecia. Hirsutism is the pathological thickening and strengthening of the hair which is characterized 25 by a masculine pattern of hair growth in children and women. Hirsutism is androgen induced, either by increased formation of androgens or by increased sensitivity of the hair follicle to androgens. The presence of the STS enzyme in keratinocytes and in skin-derived fibroblasts has been described, and the potential use of STS inhibitors for the reduction of endogenous levels of steroid 30 hormones in the skin was confirmed using known steroid sulfatase inhibitors, such as EMATE. Ad ditionally, it has been described that inhibitors of placenta steroid sulfatase also inhibit steroid sulfa tase in human keratinocyte or human skin-derived fibroblast cell lines. Therefore, STS inhibitors may be used to reduce androgen and estrogen levels in the skin, e.g. for the local treatment of an drogen-dependent disorders of the pilosebaceous unit (such as acne, seborrhoea, androgenetic 35 alopecia, hirsutism). STS inhibitors are also useful for the treatment of cancer, especially for the treatment of estrogen-and androgen-dependent cancers, such as cancer of the breast and endo metrium, squamous cell carcinoma, and cancer of the prostata.

WO 2006/125800 PCT/EP2006/062587 6 In addition, STS inhibitors may be useful for the prevention and treatment of further estro gen- or androgen-dependent diseases or disorders and/or diseases or disorders requiring the low ering of the endogeneous estrogen or androgen concentration in a generalized or tissue-specific manner, such as inflammatory and autoimmune diseases, e.g. rheumatoid arthritis, type I and 11 5 diabetes, systemic lupus erythematosus, multiple sclerosis, myastenia gravis, thyroiditis, vasculitis, ulcerative colitis, and Crohn's disease, psoriasis, contact dermatitis, graft versus host disease, ec zema, asthma and organ rejection following transplantation. STS inhibitors are also useful for the enhancement of cognitive function, especially in the treatment of senile dementia, including Alz heimer's disease, by increasing the DHEAS levels in the central nervous system. 10 Several reversible or irreversible inhibitors of the 17p-HSD1 enzyme or of the steroid sul phatase of steroidal and even non-steroidal origin are already known from the literature. The char acteristics of the inhibitory molecules of the 17-HSD1 enzyme, which mainly have a substrate or cofactor-like core structure, have been reported in the literature [reviewed in: Poirier D. (2003)]. 15 The characteristics and structure-activity relationship of known irreversible as well as reversible STS inhibitors have been reviewed in the literature [reviewed by Nussbaumer & Billich (2004) and (2003)]. Even dual inhibitors of the 17p-HSD1 enzyme and of the steroid sulphatase have been de scribed in international patent application WO 02/32409. 20 The following compounds or compound classes have already been described as 17p-HSD1 inhibitors: For example, Tremblay and Poirier describe an estradiol derivative, 16-[carbamoyl (bromo-methyl)-alkyl]-estradiol, and tested the same in respect of its inhibition of the estradiol for mation catalysed by the enzyme 17p-HSD1 [Tremblay & Poirier (1998)]. Poirier and colleagues de scribe a 6 -thiaheptan-butyl-methyl-amide derivative of estradiol as a potent and selective inhibitor 25 of the 17HSD1 enzyme [Poirier et al. (1998)]. Furthermore, Poirier and colleagues describe new derivatives of 17p-estradiol with long N-butyl, N-methyl alkylamide side chains of three different lengths (n=8, 10 or 12) at position 15, which might be potential inhibitors of the 17p-HSD1 enzyme [Poirier et al. (1991)]. Similar compounds were also disclosed within European patent application EP0367576. However, the biological activity of these compounds was only tested with regard to 30 estrogen receptor binding affinity, estrogenic and anti-estrogenic activity [Poirier et al. (1996)], but not with regard to their ability to inhibit the 17p-HSD1 enzyme. In addition, Pelletier and Poirier de scribe novel 17p-estradiol derivatives with different bromo-alkyl side chains, which might be poten tial inhibitors of the 17P-HSD1 enzyme [Pelletier & Poirier (1996)]. Sam and colleagues describe several estradiol derivatives with a halogenated alkyl side chain in 16a or 17a position of the ster 35 oidal D-ring which possess 17P-HSD1 inhibiting properties [Sam et al. (1998)]. Furthermore, the finding that some anti-estrogens, such as tamoxifen, possess weak 17p-HSD1 inhibiting properties suggested that it may be possible to develop a potent 17p-HSD1 inhibitor that is also anti estrogenic [reviewed in: Poirier D. (2003)]. Several of the aforementioned already known com- WO 2006/125800 PCT/EP2006/062587 7 pounds also display anti-estrogenic properties (e.g. the 6p-thiaheptan-butyl-methyl-amide deriva tive of estradiol described by Poirier and colleagues [Poirier et al. (1998)]). None of the aforemen tioned compounds has been clinically used so far. 5 Furthermore, the international patent application WO 2004/085457 discloses a variety of es tron derivatives with different substituents in C2, C3, C6, C16 and/or C17 position as potent 17p HSD1 inhibitors. For some of the compounds it was shown that the substitution of steroid based 17p-HSD1 inhibitors at the C2 position with small hydrophobic groups renders the compounds less estrogenic and are favourable for 17p-HSD1 over 17p-HSD2 discrimination [Lawrence et al 10 (2005)]. The international application WO 2005/047303, published on the filing date of the priority ap plication of the present invention, discloses new 3, 15 substituted 17p-estradiol derivatives with dif ferent kind of side chains at position 15, which are potent and selective 17p-HSD1 inhibitors. 15 Additional compounds representing potential 17p-HSD1 inhibitors were disclosed within in ternational applications WO 2006/003012 and WO 2006/003013 in the form of novel 2-substituted D-homo-estra-1,3,5(10)-trienes and novel 2-substituted estra-1,3,5(10)-trien-17-ones. 20 The synthesis of different B-, C- and D-ring substituted estradiol carboxylic esters was de scribed by Labaree et al. [Labaree et al. (2003)]. However, these esters were only analysed with regard to their estrogenic potential. The related international patent application WO 2004/085345 discloses 15a substituted estradiol compounds bearing a -(CH 2 )m-CO-0-R side chain, wherein R is H, a C-Cs alkyl group, optionally substituted with at least one halogen group, such as CH 2

CH

2 F, or 25 other group (e.g. CH 2

CHF

2 , CH 2

CF

3 or CF 3 group); and m is from 0-5. These 15a estradiol esters are described as locally active estrogens without significant systemic action. Furthermore, international application WO 2006/027347 discloses 15p substituted estradiol derivatives having selective estrogen receptor activity towards the estrogen receptor a-subtype. 30 Several compounds and compound classes have already been identified as STS inhibitors. They all share the common structural feature of an aromatic ring bearing a substituent that mimics the phenolic A-ring of the enzyme substrate, estrone-sulphate. On the development of steroidal in hibitors, a wide variety of chemical groups have been introduced at C3, of which the 3-0-sulfamate 35 was found to be the most potent for the estrone molecule. The resulting compound, estrone-3-0 sulfamate ("EMATE") led to the identification of the aryl-O-sulphamate structure as an active phar macophore required for potent inhibition of STS (as disclosed in international patent application WO 93/05064). EMATE was shown to inhibit steroid sulphate activity in a time-and concentration- WO 2006/125800 PCT/EP2006/062587 8 dependent manner and was active in vivo on oral administration. It was however revealed to be highly estrogenic which raised the need to design STS inhibitors devoid of agonist activity on the human estrogen receptor. For example, the recently published international patent application WO 2004/085459 discloses a variety of estron derivatives with different subsituents in C2, C3, C4 5 and/or C17 position as potent STS inhibitors. Accordingly, there is still a need for the development of compounds which are suited for the treatment and/or prevention of steroid hormone dependent diseases or disorders such as breast cancer, endometriosis and uterine leiomyomas by selectively inhibiting the 17p-HSD1 enzyme and 10 preferably additionally inhibiting the STS enzyme, while desirably failing to substantially inhibit other members of the 17p-HSD protein family or other catalysts of sex steroid degradation or acti vation. In particular, it is an aim of the present invention to develop selective inhibitors of the 17p HSD1 enzyme, whereby in addition the compounds have no or only pure antagonistic binding af finities to the estrogen receptor (both subtypes a and P) and have favourably no residual activity on 15 the 17P-HSD2 enyme. Furthermore, an increased metabolic stability of the compounds, in particu lar of the C1 7 keto position of the steroidal core, would be desirable, in order to prevent conversion of the estron to the respective estradiol derivative, which shows less inhibitory potential on the 17p HSD1 enzyme. 20 SUMMARY OF THE INVENTION Therefore, it is an object of the present invention to develop novel inhibitors of the enzyme 17p-HSD1 and preferably also of the enzyme STS, which have valuable pharmacological proper ties and which are suited for the treatment of estrogen dependent diseases and disorders. 25 It has now been found that novel 3, 15 substituted estrone derivatives bearing a side chain of the amide, ester, carbonyl, hydrazone, alcohol, ether, urea, carbamate, "retro"-amide, sulfonyl urea, sulfamide, sulfamate, "retro"-sulfonamide, "retro"-carbamate, "retro"-ester or sulfonylcar bamate type in position C15 and being additionally modified by substitution in position C2, C3, C16 30 and/or C17 position of the estron core, would be valuable in therapy, especially in the treatment or prevention of steroid hormone dependent diseases or disorders requiring the lowering of the en dogeneous estradiol concentration, in humans and other mammals. In particular, compounds of formula (1) represent potent inhibitors of the 17p-HSD1 enzyme and optionally of the STS enzyme, and possess valuable pharmacological properties for the treatment and/or prophylaxis of malignant 35 steroid dependent diseases or disorders such as breast cancer, prostate carcinoma, ovarian can cer, uterine cancer, endometrial cancer and endometrial hyperplasia, but also for the treatment and/or prophylaxis of benign steroid dependent diseases or disorders such as endometriosis, uter ine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhoea, menorrhagia, metrorrhagia, pros- WO 2006/125800 PCT/EP2006/062587 9 tadynia, benign prostatic hyperplasia, urinary dysfunction or lower urinary tract syndrome. Further estrogen-dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts. The compounds of the present invention have been developed as im 5 proved inhibitors of the enzyme 17p-HSD1, in addition showing no or only pure antagonistic bind ing affinities to the estrogen receptor (both subtypes ax and P) and having favourably no residual activity on the 17-HSD2 enyme, and/ or showing an increased metabolic stability of the C1 7 keto function of the steroidal core. 10 Accordingly, the present invention relates to a compound having the structural formula I R13 R12 R14 H R10(I) O y A 'Y R2 wherein (i) X represents: (a) a bond, 15 (b) -NH-, or (c) -0-; A represents: (a) -CO-, or (b) under the proviso that X represents -NH-, A represents -SO 2 -; 20 Y represents: (a) -NR 4 -, (b) -0-, under the proviso that X represents a bond or -NH-, (c) a bond, (d) -NH-SO 2 - , under the proviso that X represents -NH- and A represents 25 -co-, (e) -NH-SO 2 -

NR

4 -, under the proviso that X represents -0-, or (f) -NH-NR 4 -, under the proviso that X represents a bond; or (ii) -X-A-Y- together represent -0-; 30 and wherein

R

1 is selected from: WO 2006/125800 PCT/EP2006/062587 10 (a) -H, (b) -(C1-C 6 )alkyl, which is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , or

-COOR

6 ; the number of said substituents being up to three for halogen, and up to two for any combination of said halogen, nitril, -OR 6 , -SR 6 , or -COOR 6 moieties, 5 (c) -phenyl, which is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , -R 6 , or -COOR , the number of said substituents being up to perhalo for halogen, and up to two for any combination of said halogen, nitril, -OR 6 , -SR 6 , -R 6 or -COOR 6 moieties, (d) -(C1-C 4 )alkyl-phenyl, in which the alkyl portion is optionally substituted with up to three halogens; and the phenyl portion is optionally substituted with halogen, nitril, -OR, 10 -SR , -R or -COOR , the number of substituents on said phenyl portion being up to perhalo for halogen, and up to two for any combination of said halogen, nitril, -OR, SR 6 , -R 6 or -COOR 6 moieties, (e) -SO 2

-NR

3

R

3 , (f) -CO-NR 3

R

3 , 15 (g) -PO(OR )-R 3 , (h) -PS(OR )-R 3 , (i) -PO(OR 6

)-O-R

3 (j) -S0 2

-R

3 , and (k) -S0 2 -0-R 3 ; 20 wherein

R

6 represents H, -(C1-C 4 )alkyl or halogenated -(C1-C 4 )alkyl;

R

3 and R3' are independently selected from H, alkyl, aryl and arylalkyl, or R 3 and R3' form to gether with the nitrogen atom, to which R 3 and R3' are attached, a heterocyclic 4-, 5-, 6-, 7 25 or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, 0 or S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; and

R

1 6 represents -H, alkyl, or arylalkyl; 30 R2 and R4 are independently selected from: (a) -H, wherein if X represents a bond, A represents -CO- and Y represents -0- or a bond, then R2 is different from -H; (b) optionally substituted alkyl, 35 (c) optionally substituted acyl, under the proviso that Y represents -NH-NR 4 -, (d) optionally substituted aryl, (e) optionally substituted heteroaryl, and (f) optionally substituted cycloheteroalkyl, or, under the proviso that Y represents -NR 4 -, -N H-N R 4 - or -NH-SO 2

-NR

4

-,

WO 2006/125800 PCT/EP2006/062587 11 R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aro matic; which optionally contains up to three additional heteroatoms selected from N, 0 or S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each 5 being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or the ring-system is optionally substituted; the substituents R 10 , R", R 1 2 and R 1 3 together with the carbon atoms, to which they are attached, form a structure -CR1 3 R1 2 -CR R1 0 -, wherein 10 (a) R 1 0 and R" both represent -H and R 1 2 and R 13 together represent a group selected from =0, =CF 2 , =N-0-alkyl, and =N-OH, or (b) R 1 0 and R1 both represent -H, and R and R 1 3 both individually represent -F, or (c) R 1 0 , R" and R 13 all represent -H, and R 12 is selected from -OH, -CN, -F, -CF 3 , and

-CF

2 H, or 15 (d) R 1 0 represents -H, R" together with R 1 3 forms a bond, and R 1 2 is selected from -CN, -F,

-CF

3 , and -CF 2 H; or (e) R 10 represents -H, R" represents -CHO, and R 1 2 and R 1 3 together represent =0; or, the substituents R 1 0 , R", R 1 2 and R 1 3 together with the carbon atoms, to which R 10 , R", R 12 and 20 R are attached, form a heterocyclic 5- or 6-membered ring, which is partly unsaturated or aromatic, which contains one, two or three heteroatoms independently selected from N, 0 or S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, wherein one heteroatom is directly attached to the C17 C-atom of the steroidal core; and which ring is optionally substituted with an alkyl group; 25 R 1 represents an alkyl, alkoxy, or alkoxy-alkyl group, or under the proviso that at least (i) R 1 represents -SO 2

-NR

3

R

3 ', -CO-NR 3

R

3 ', -PO(OR 6

)-R

3 , -PS(OR 6

)-R

3 , -PO(OR 16

)

OR

3 , -S0 2

-R

3 , or -S0 2

-OR

3 ; or 30 (ii) R 10 or R" is different from -H, or (iii) R 1 0 , R" and R 13 all represent -H, and R 12 does not represent -OH, or (iv) R and R 13 together do not represent =0, then R may represent -H; and 35 n represents 0, 1, 2, 3, 4, 5 or 6, wherein, if X represents -NH- or -0-, then n is different from 0, and all stereoisomers, pharmacologically acceptable salts and prodrugs thereof.

WO 2006/125800 PCT/EP2006/062587 12 Accordingly, the present inventions relates to a compound of the general formula 1, wherein -X-A-Y- together represent a group selected from (a) -CO-NR 4 -, (b) -CO-O-, 5 (c) -CO-, (d) -CO-NH-NR 4 -, (e) -NH-CO-NR 4 -, preferably -NH-CO-NH-, (f) -NH-CO-0-, (g) -NH-CO-, 10 (h) -NH-CO-NH-SO 2 -, (i) -NH-SO 2

-NR

4 -, preferably -NH-SO 2 -NH-, (j) -NH-SO 2- O-, (k) -NH-SO 2 (1) -O-CO-N R 4 -, preferably -O-CO-N H-, 15 (m) -O-CO-, (n) -O-CO-NH-SO 2-

NR

4 -, and (o) -0-; n represents 1, 2, 3, 4, 5 or 6, or, if -X-A-Y- represents -CO-NR 4 -, -CO-O-, -CO-, or -CO 20 NH-NR 4 -, then n may also represent 0;

R

1 is selected from: (a) -H, (b) -(C1-C 6 )alkyl, which is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , or -COOR 6 ; 25 the number of said substituents being up to three for halogen, and up to two for any com bination of said halogen, nitril, -OR 6 , -SR 6 , or -COOR 6 moieties, (c) -phenyl, which is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , -R 6 , or -COOR 6 , the number of said substituents being up to perhalo for halogen, and up to two for any combination of said halogen, nitril, -OR 6 , -SR 6 , -R 6 or -COOR 6 moieties, 30 (d) -(C1-C 4 )alkyl-phenyl, in which the alkyl portion is optionally substituted with up to three halogens; and the phenyl portion is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , -R or -COOR, the number of substituents on said phenyl portion being up to perhalo for halogen, and up to two for any combination of said halogen, nitril, -OR 6 , -SR 6 , -R 6 or -COOR moieties, 35 (e) -SO 2 -

NR

3

R

3 , (f) -CO-NR 3

R

3 , (g) -PO(OR' 6

)-R

3 , (h) -PS(OR' 6

)-R

3 , (i) -PO(OR 6

)-O-R

3 WO 2006/125800 PCT/EP2006/062587 13 (j) -S0 2

-R

3 , and (k) -S0 2 -0-R 3 ; wherein

R

6 represents H, -(C1-C 4 )alkyl or halogenated -(C1-C 4 )alkyl; 5 R 3 and R 3 ' are independently selected from H, alkyl, aryl and arylalkyl, or R 3 and R3' form to gether with the nitrogen atom, to which R 3 and R3' are attached, a heterocyclic 4-, 5-, 6-, 7 or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, 0 and S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 10 2; and

R

1 6 represents -H, alkyl, or arylalkyl; R2 and R4 are independently selected from: (a) -H, 15 (b) optionally substituted alkyl, (c) optionally substituted acyl, under the proviso that -X-A-Y- represent -CO-NH-NR 4 -, (d) optionally substituted aryl or arylalkyl, (e) optionally substituted heteroaryl or heteroarylalkyl, and (f) optionally substituted cycloheteroalkyl or cycloheteroalkyl-alkyl, 20 or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, 0 and S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or 25 the ring-system is optionally substituted; the substituents Rio, R", R 1 2 and R 1 3 together with the carbon atoms, to which they are attached, form a structure R13 R1 11 which is selected from the group of O CF F CHF2 F F

CF

3

CHF

2 F CF 3 and 30 WO 2006/125800 PCT/EP2006/062587 14 or, the substituents Rio, R", R 1 2 and R 1 3 together with the carbon atoms, to which they are at tached, form a heterocyclic 5- or 6-membered ring, which is partly unsaturated or aromatic, which contains one, two or three heteroatoms independently selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, 5 wherein one heteroatom is directly attached to the C1 7 C-atom of the steroidal core; and which ring is optionally substituted with an alkyl group; R 1 represents an alkyl, alkoxy, or alkoxy-alkyl group, or R 1 may also represent -H, under the proviso that at least 10 (i) R 1 represents -SO 2

-NR

3

R

3 ', -CO-NR 3

R

3 ', -PO(OR 6

)-R

3 , -PS(OR 6

)-R

3 , -PO(OR 16

)

OR

3 , -S0 2

-R

3 , or -S0 2

-OR

3 ; or (ii) R13 O R is different from and all pharmacologically acceptable salts thereof. 15 In one embodiment, the present invention relates to a compound of the general formula 1, which is an optically pure 15ax enantiomer having the formula (II) R13 R12 R1R11 R10(II) H H ) X A Y'R2 or a physiologically acceptable salt thereof. In a further embodiment, the present invention 20 relates to the 15ax enantiomer having formula (II), wherein n represents 1, 2, 3 or 4. In another embodiment, the present invention relates to a compound of the general formula 1, which is an optically pure 15 enantiomer having the formula (111) R13 R12 R11 R14 H R10(l) H H OXA '-,R2 25 or a physiologically acceptable salt thereof. In a further embodiment, the present invention relates to the 15P enantiomer having formula (111), wherein n represents 2, 3, 4, or 5.

WO 2006/125800 PCT/EP2006/062587 15 One embodiment of the present invention relates to compounds of formula 1, wherein

R

1 is selected from: (a) -SO 2

-NR

3

R

3 , (b) -CO-NR 3

R

3 , 5 (c) -PO(OR )-R 3 (d) -PS(OR )-R 3 (e) -PO(OR 6

)-O-R

3 , (f) -S02-R3; and (g) -SO 2 -O-R3; 10 wherein

R

3 and R 3 are independently selected from H, alkyl, aryl and arylalkyl, or R 3 and R3' form to gether with the nitrogen atom, to which R 3 and R3' are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aro matic; which optionally contains up to three additional heteroatoms selected from N, 0 15 or S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; and

R

1 6 represents -H, alkyl, or arylalkyl. In a preferred subgroup of this embodiment, R 1 0 and R" both represent -H and R and R 1 3 20 together represent =0; and/or R represents -H, -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C1-C 8 )alkyl O-(C1-C 8 )alkyl. In this embodiment, R 3 and R 3 are preferably independently selected from -H, -(C1-C)alkyl, phenyl and -(C1-C 4 )alkyl-phenyl, or 25 R 3 and R3' together with the nitrogen atom, to which R 3 and R3' are attached, form a hetero cyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is selected from the group consisting of -N -N o -N S -N N / o / S N -N -N -N -N -NO and -N /- n ~N\ , and

R

1 6 represents -H, -(C1-C 4 )alkyl, or -(C1-C 4 )alkyl-phenyl, preferably -H. 30 Particularly preferred compounds are those, wherein R 1 is selected from -SO 2

-NR

3

R

3 , _

CO-NR

3

R

3 ', -PO(OR 6

)-R

3 , and -S0 2

-R

3 ; preferably -SO 2

-NR

3

R

3 ', wherein R 3 and R3' together with the nitrogen atom, to which R 3 and R3' are attached, form a heterocyclic ring selected from WO 2006/125800 PCT/EP2006/062587 16 morpholine, thiomorpholine and piperazyl, and even more preferred -SO 2

-NH

2 . Preferably, those compounds carry a substituent R representing -H. One embodiment of the present invention relates to compounds of formula 1, wherein R 1 5 represents an alkyl, alkoxy, or alkoxy-alkyl group. In a further embodiment, the invention relates compounds of the general formula 1, wherein

R

1 represents -H, (C1-C 4 )alkyl, or -(C1-C 4 )alkyl-phenyl;

R

1 0 and R 1 1 both represent -H and R 1 2 and R 1 3 together represent =0; and 10 R 4 represents -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C1-C 8 )alkyl-O-(C1-C)akyl. In this context, mostly preferred are compounds of the general formula 1, wherein R repre sents -(C1-C4)alkyl, -O-(C1-C4)alkyl, or -(C1-C4)alkyl-O-(C1-C4)alkyl, preferably ethyl, propyl, me thoxyethyl, methoxy, ethoxy or methoxyethoxy, and R 1 is independently selected from -H, (C1 15 C 4 )alkyl, preferably methyl, and phenyl(C1-C 4 )alkyl, preferably benzyl, most preferred -H. A further preferred embodiment of the present invention relates to compounds of the general formula 1, wherein the substituents Rio, R", R 1 2 and R 13 together with the carbon atoms, to which they are attached, form a structure R13 R1 11 20 R1o which is selected from the group of

CF

2 F CHF 2 F F CF CHF F CF3 and In a subgroup of this embodiment, additionally R 14 represents -H, -(C1-C 8 )alkyl, -O-(C1

C

8 )alkyl, or -(C1-C 8 )alkyl-O-(C1-C)aky, and R represents -H, (C1-C 4 )alkyl, or -(C 1

-C

4 )alkyl 25 phenyl; In this context are those compounds preferred, wherein the substituents Rio, R", R 12 and

R

13 together with the carbon atoms, to which they are attached, form a structure WO 2006/125800 PCT/EP2006/062587 17 R13 R1 11 which is selected from the group of F CF 2 F CF 3 F and Preferably, those compounds carry substituents R and R which are each individually -H. 5 In an additional embodiment of the present invention, compounds of the general formula I are disclosed, wherein the substituents Rio, R", R and R 13 together with the carbon atoms, to which Rio, R", R1 and R 1 3 are attached, form a heterocyclic 5- or 6-membered ring, which is partly un saturated or aromatic, which contains one, two or three heteroatoms independently 10 selected from N, 0 or S, the number of N atoms being 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2, wherein one heteroatom is directly attached to the C17 C-atom of the steroidal core; and which ring is optionally substituted with an alkyl group; and 15 In a subgroup of this embodiment, additionally R 1 represents -H, (C1-C 4 )alkyl, or -(C 1 C 4 )alkyl-phenyl, and R represents -H, -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C 1

-C

8 )alkyl-O-(C 1 C 8 )alkyl. In this context, the present invention preferably relates to compounds, wherein the substitu 20 ents Rio, R", R 12 and R 1 3 together with the carbon atoms, to which Ri , R", R 1 2 and R 13 are at tached, form a heterocyclic 5- or 6-membered ring to provide a compound of one of the following formulas R15 N R N_'N R14 .H R14 .H H H | H H 0 X A R2 OR X A YR2 O- N O_ R14 .H .R14 H WH H )WH H ) OX, A R2, or O X, A Y R2 WO 2006/125800 PCT/EP2006/062587 18 wherein R 1 5 represents -H or -(C1-C 4 )alkyl, preferably methyl or -H. Preferably, those com pounds carry substituents R1 and R each individually representing -H. One embodiment of the present invention relates to compounds of formula 1, wherein 5 e R1 is selected from: (a) -H, (b) -(C1-C 6 )alkyl, (c) -phenyl, (d) -(C1-C 4 )alkyl-phenyl, 10 (e) -SO 2

-NR

3

R

3 , (f) -CO-NR 3

R

3 , (g) -PO(OH)-R 3 , (h) -PS(OH)-R 3 , (i) -PO(OH)-O-R 3 15 (j) -S0 2

-R

3 , and (k) -S0 2

-O-R

3 ; wherein

R

6 represents H, -(C1-C 4 )alkyl or halogenated -(C1-C 4 )alkyl;

R

3 and R 3 ' are independently selected from -H, -(C1-C)alkyl, phenyl and -(C1-C 4 )alkyl 20 phenyl, or R 3 and R3' together with the nitrogen atom, to which R 3 and R3' are at tached, form a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is selected from the group consisting of -N -N O -N S -N N 0 S N -N -N -N -N NO and N even more preferred selected from morpholine, thiomorpholine and piperazyl, 25 e the substituents Rio, R", R 12 and R 13 together with the carbon atoms, to which they are at tached, form a structure R13 R1 11 R, which is selected from the group of WO 2006/125800 PCT/EP2006/062587 19 0 CF 2 F CHF 2 F F

CF

3

CHF

2 F CF 3 and or, the substituents R 10 , R", R 12 and R 13 together with the carbon atoms, to which R 1 0 , R",

R

12 and R 13 are attached, form a heterocyclic 5- or 6-membered ring to provide a compound of one of the following formulas R15 N _ N R14 H R14 H H Ho| H R n R!, )n 5 A R2 O X'A NR2 O- N /_ O R14 H R14 .H RK ( H n R , ( )n 0 X A R 2 X A R2 , or wherein R 15 represents -H or -(C1-C 4 )alkyl; and R 4 represents -(C1-C 4 )alkyl, -O-(C1-C4)alkyl, or -(C-C 4 )alkyl-O-(C1-C 4 )alkyl, or R may also represent -H, under the proviso that at least 10 (i) R 1 represents -SO 2

-NR

3

R

3 ', -CO-NR 3

R

3 ', -PO(OH)-R 3 , -PS(OH)-R 3 , -PO(OH)-OR 3 , -S0 2

-R

3 , or -S0 2

-OR

3 ; or (ii) R13 O R 1 1 is different from 15 A further embodiment of the present invention relates to compounds of the formula (1), wherein

R

1 represents -H or -SO 2

-NH

2 , the substituents R 1 0 , R", R 12 and R 13 together with the carbon atoms, to which they are at tached, form a structure WO 2006/125800 PCT/EP2006/062587 20

R

1 3

R

1 2 11 , which is selected from the group of 0 F CF 2 F CF 3 H F N andN ;and R14 represents -H, -(C1-C 4 )alkyl, -O-(C1-C 4 )alkyl, or -(C1-C 4 )alkyl-O-(C1-C 4 )alkyl. R14 in particular may represent -H, when at least 5 (i) R 1 represents -SO 2

-NH

2 , or (ii) R13 O

R

1 1 is different from R1o A preferred embodiment of the present invention relates to compounds of formula 1, wherein 10 R2 and R4 are independently selected from: (a) -H, wherein if -X-A-Y- together represents -CO-0- or -CO-, then R2 is different from -H, (b) -(C1-C 1 2 )alkyl, optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, thiol, nitrile, alkoxy, aryloxy, arylalkyloxy, 15 amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyl, acylamino, aryl, which aryl is optionally substituted with up to three substituents independently se lected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C 6 )alkyl, halogenated (C1-C 6 )alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, 20 nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylthio, aryl thio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms selected 25 from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being being 0, 1 or 2; heteroaryl, which heteroaryl is optionally substituted with up to three substituents inde pendently selected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C 6 )alkyl, halogenated (C1-C 6 )alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C 1 30 C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1- WO 2006/125800 PCT/EP2006/062587 21

C

6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino, aryl-(C1-C 4 )-alkyl and aryl; whereby each aryl group is optionally substituted with up to three substituents in dependently selected from the group consisting of hydroxyl, halogen, (C1 5 C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-C 6 )alkyl and halogenated (C1

C

6 )alkoxy; and cycloheteroalkyl, which cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C1-C 8 )-alkyl, aryl, aryl-(C1-C 4 )-alkyl, hydroxyl, (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, 10 sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, and acylamino, whereby each aryl group is optionally substituted with up to three substituents in dependently selected from the group consisting of hydroxyl, halogen, (C1

C

4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, and halogenated (C1 15 C 4 )-alkoxy); (c) acyl -(C=O)-R', wherein R' represents hydrogen, (C1-C 4 )alkyl, aryl, or aryl-(C1-C 4 )alkyl, or heteroaryl-(C1-C 4 )alkyl; which aryl or aryl-(C1-C 4 )alkyl is optionally substituted in the aryl, preferably phenyl, moi ety with up to three substituents independently selected from the group consisting 20 of hydroxyl, halogen, (C1-C 4 )alkoxy, (C1-C 4 )-alkyl or halogenated (C1-C 4 )alkyl; (d) aryl, which aryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C)alkyl, halo genated (C1-C)alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, 25 nitro, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylsulfonyl, arylsulfonyl, (C1-C 6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 30 membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or2; (e) heteroaryl, which heteroaryl is optionally substituted with up to three substituents independently se 35 lected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-C)alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, arylsulfoxy, carboxyl, aryloxy, arylalkyloxy, (C1

C

6 )alkylsulfonyl, arylsulfonyl, (C 1

-C

6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino, aryl-(C1-C 4 )-alkyl and aryl, WO 2006/125800 PCT/EP2006/062587 22 whereby each aryl group is optionally substituted with up to three substituents in dependently selected from the group consisting of hydroxyl, halogen, (C1

C

6 )alkoxy, (C1-C)alkyl, halogenated (C1-C 6 )alkyl and halogenated (C1

C

6 )alkoxy; or 5 (f) cycloheteroalkyl, which cycloheteroalkyl is optionally substituted with up to three substituents independ ently selected from the group consisting of oxo, (C1-C 14 )-alkyl, aryl, aryl-(C1-C 4

)

alkyl, hydroxyl, (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, sulfamoyl, sul fonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylthio, arylthio, arylalkylthio, 10 amino, amido, acyl, and acylamino, whereby each aryl group is optionally further substituted with up to three substitu ents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, and halogenated (C1-C 4 )-alkoxy; 15 or wherein, R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated or partly unsatu rated; which optionally contains up to three additional heteroatoms selected from N, 0 and S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each be ing 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, 20 wherein the ring or the ring-system is optionally substituted (i) with up to three substituents independently selected from the group consisting of (C 1

-C

8

)

alkyl, halogen, hydroxyl, carboxyl, thiol, nitrile, (C1-C)-alkoxy, carboxyl-(C1-C 6 )alkyl, ary loxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, aryl, aryl-(C1-C 4 )-alkyl, heteroaryl, and cycloheteroalkyl, 25 wherein the (C1-C 8 )-alkyl group is optionally substituted with up to three substituents in dependently selected among hydroxyl, halogen, (C1-C 4 )-alkoxy, or halogenated (C1-C 4 )-alkoxy, whereby the alkyl-chain of the (C1-C 4 )-alkoxy moiety is optionally substituted with hydroxyl; 30 wherein the aryl group or aryl moiety is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C 1

-C

4

)

alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, halogenated (C1-C 4 )-alkoxy and carboxyl-(C1-C 6 )alkyl, or wherein the aryl moiety is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a satu 35 rated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N at oms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; wherein the heteroaryl group is optionally substituted with up to three substituents inde pendently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, WO 2006/125800 PCT/EP2006/062587 23 (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, halogenated (C1-C 4 )-alkoxy) and car boxyl-(C1-C 6 )alkyl; wherein the cycloheteroalkyl is optionally substituted with up to three substituents inde pendently selected from the group consisting of oxo, (C1-C 8 )-alkyl, aryl, aryl-(C1 5 C 4 )-alkyl, hydroxyl, (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, and carboxyl, whereby each aryl group is optionally further substituted with up to three substitu ents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, and halogenated (C1-C 4 )-alkoxy); or 10 (ii) by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N atoms be ing 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, whereby the cyclic ring system is optionally substituted by up to two substituents inde 15 pendently selected from oxo, (C1-C)-alkyl, aryl and aryl-(C1-C 4 )-alkyl; and wherein n represents (a) 1, 2, 3, 4, 5 or 6, if -X-A-Y- together represent -NH-CO-NH-, -NH-CO-0-, -NH-CO , -NH-CO-NH-SO 2 -, -NH-SO 2- NH-, -NH-SO 2- O-, -NH-SO 2- , -0-CO-NH-, -0 20 CO-, -O-CO-NH-SO 2

-NR

4 -, or -0-, or (b) 0, 1, 2, 3, 4, or 5, if -X-A-Y- together represent -CO-NR 4 -, -CO-O-, -CO-, or -CO

NH-NR

4 -. In one preferred embodiment of the present invention, the residues R2 and R4 in the com 25 pounds of the general formula I may independently represent -H, wherein, if -X-A-Y- together represents -CO-0- or -CO-, then R2 is different from -H. In a further embodiment of the present invention relates to compounds of formula 1, wherein R2 and R4 are independently selected from: 30 (a) -(C1-C 12 )alkyl, optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, nitrile, -O-R 7 ; -O-Arl, -O-(C1-C 4 )alkyl Arl, alkylamino, alkylamido, -S-R 7 , -S-Ar, -S-(C1-C 4 )aky-Ar, -(C=O)-OR, aryl, het eroaryl, and cycloheteroalkyl, wherein the aryl is optionally substituted with up to three substituents independently se 35 lected from the group consisting of halogen, hydroxyl, (C 1

-C

6 )alkoxy, (C 1

-C

6 )alkyl, halogenated (C 1

-C

6 )alkyl, halogenated (C 1

-C

6 )alkoxy, -(C 1

-C

6 )alkyl-(C=O)-OR 8 , nitrile, sulfamoyl, -(C=O)-OR, -0-Ar, -O-(C 1

-C

4 )aky-Ar, (C 1

-C

6 )alkylthio, -S Ar 1 , -S-(C1-C 4 )aky-Ar, alkylamino, and alkylamido; or wherein the aryl is option ally substituted by two groups which are attached to adjacent carbon atoms and WO 2006/125800 PCT/EP2006/062587 24 are combined into a saturated cyclic 5 or 6 membered ring system, optionally con taining up to three heteroatoms selected from N or 0, the number of N atoms being 0, 1, 2 or-3 and the number of 0 atoms each being 0, 1, or 2; wherein the heteroaryl is optionally substituted with up to three substituents independ 5 ently selected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1 C)-alkyl, halogenated (C1-C)alkyl, halogenated (C1-C 6 )alkoxy, -(C1-C 6 )alkyl

(C=O)-OR

8 , nitrile, sulfamoyl, -(C=O)-OR, -0-Ar, -O-(C1-C 4 )alkyl-Ar1, (C 1

-C

6

)

alkylthio, -S-Ar, -S-(C1-C 4 )alkyl-Ar1, alkylamino, alkylamido, -(C 1

-C

4 )alkyl-Ar and Ar 1 ; and 10 wherein the cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C1-C)-alkyl, Ar,-(C 1 C 4 )-alkyl-Arl, hydroxyl, (C1-C 6 )alkoxy, -(C 1

-C

6 )alkyl-(C=O)-OR, nitrile, -(C=O)

OR

8 , -0-Ar, -O-(C1-C 4 )alkyl-Ar, (C1-C 6 )alkylthio, -S-Arl, -S-(C1-C 4 )alkyl-Ar 1 , alkylamino and alkylamido; 15 (b) aryl, which aryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C 1

-C

6 )alkoxy, (C 1

-C

6 )alkyl, haloge nated (C 1

-C

6 )alkyl, halogenated (C 1

-C

6 )alkoxy, -(C 1

-C

6 )alkyl-(C=O)-OR, nitro, nitrile, sulfamoyl, -(C=O)-OR 8 , -(C=O)-R 8 , -0-Ar, -0-(C 1

-C

4 )alkyl-Ar, (C 1

-C

6

)

20 alkylthio, -S-Ar, -S-(C 1

-C

4 )alkyl-Ar, (C 1

-C

6 )alkylsulfonyl, -SO 2 -Ar, alkylamino, alkylamide, -NH-CO-R 8 , Ar and heteroaryl; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, op tionally containing up to three heteroatoms selected from N and 0, the number of 25 N atoms being 0, 1, 2 or 3 and the number of 0 atoms being 0, 1 or 2; (c) heteroaryl, which heteroaryl is optionally substituted with up to three substituents independently se lected from the group consisting of halogen, hydroxyl, (C 1

-C

6 )alkoxy, (C 1

-C

6 )alkyl, halogenated (C 1

-C

6 )alkyl, halogenated (C 1

-C

6 )alkoxy, -(C 1

-C

6 )alkyl-(C=O)-OR 8 , 30 nitrile, sulfamoyl, -(C=O)-OR, -0-Ar, -O-(C 1

-C

4 )alkyl-Ar, (C 1

-C

6 )alkylthio, -S Ar 1 , -S-(C 1

-C

4 )alkyl-Ar, (C 1

-C

6 )alkylsulfonyl, -SO 2 -Ar, alkylamino, alkylamido, (C 1

-C

4 )alkyl-Ar and Ar 1 ; or (d) cycloheteroalkyl, which cycloheteroalkyl group is optionally substituted with up to three substituents inde 35 pendently selected from the group consisting of oxo, (C 1

-C

8 )-alkyl, Ar 1

,-(C

1 C 4 )alkyl-Ar, hydroxyl, (C 1

-C

6 )alkoxy, -(C 1

-C

6 )alkyl-(C=O)-OR, nitrile, -(C=O)

OR

8 , -0-Ar, -O-(C 1

-C

4 )alkyl-Ar, (C 1

-C

6 )alkylthio, -S-Ar, -S-(C 1

-C

4 )alkyl-Ar 1 , alkylamino and alkylamido; wherein WO 2006/125800 PCT/EP2006/062587 25

R

7 represents (C1-C)alkyl, optionally substituted with up to three hydroxy groups in the alkyl chain or halogenated (C1-C)alkyl,

R

8 represents hydrogen, (C1-C 4 )alkyl, phenyl, or (C1-C 4 )alkyl-phenyl, wherein the phenyl moiety is optionally substituted with up to three substituents independently selected from 5 the group consisting of hydroxyl, halogen, (C1-C 4 )alkoxy, (C1-C 4 )-alkyl, halogenated (C1

C

4 )alkyl and halogenated (C1-C 4 )alkoxy; and Ar represents phenyl or naphthyl, which are optionally substituted with up to three substitu ents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, or halogenated (C1-C 4 )-alkoxy; 10 or wherein the ring or ringsystem formed by R 2 and R 4 together with the nitrogen atom, to which R 2 and R 4 are attached, is selected from the group consisting of N _N 0 -N S -N N -N 0 S N -N _N _N -N -N -N N -N N and NN N wherein the ring or the ring-system is optionally substituted 15 (i) with up to three substituents independently selected from the group consisting of (C 1

-C

8

)

alkyl, oxo, hydroxyl, (C1-C 6 )alkoxy, -(C 1

-C

6 )alkyl-(C=O)-OR 8 ', nitrile, -(C=O)-OR 8 ', -0 Ar 2 , -O-(C1-C 4 )alkyl-Ar2, (C1-C 6 )alkylthio, alkylamino, alkylamido, aryl, aryl-(C1-C 4 )alkyl, heteroaryl, and cycloheteroalkyl, wherein the aryl and aryl-(C1-C 4 )alkyl group are optionally substituted in the aryl moiety 20 with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, halo genated (C1-C 4 )-alkoxy and carboxyl-(C1-C 4 )alkyl, or wherein the aryl moiety is op tionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 mem 25 bered ring system, optionally containing up to three heteroatoms selected from N, O and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S at oms each being 0, 1 or 2; and WO 2006/125800 PCT/EP2006/062587 26 wherein the (C1-C 8 )-alkyl group is optionally substituted with up to three substituents in dependently selected among hydroxyl, halogen, halogenated (C1-C 4 )-alkoxy or (C1

C

4 )-alkoxy, whereby the alkyl-chain of the (C1-C 4 )-alkoxy moiety is optionally substituted with 5 up to three hydroxyl; wherein the heteroaryl is optionally substituted with up to three substituents independ ently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1

C

4 )-alkoxy, halogenated (C1-C 4 )-alkyl, halogenated (C1-C 4 )-alkoxy) and carboxyl (C1-C 6 )alkyl; and 10 wherein the cycloheteroalkyl is optionally substituted with up to three substituents inde pendently selected from the group consisting of oxo, (C1-C)-alkyl, hydroxyl, (C1

C

6 )alkoxy, -(C=O)-OR 9 , and -(C1-C 6 )alkyl-(C=O)-OR 9 ; or (ii) by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8-membered ring system, optionally 15 containing up to three heteroatoms selected from N, 0 and S, the number of N atoms be ing 0, 1, 2 or-3 and the number of 0 and S atoms each being 0, 1 or 2, whereby the cyclic ring system is optionally substituted by up to three substitutents inde pendently selected from oxo, (C1-C)-alkyl, aryl and aryl-(C1-C 4 )-alkyl. wherein 20 Ar 2 represents phenyl or naphthyl, which are optionally substituted with up to three substitu ents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, or halogenated (C1-C 4 )-alkoxy

R

9 represents hydrogen, (C1-C 4 )alkyl, phenyl, or (C1-C 4 )alkyl-phenyl; whereby the phenyl is optionally substituted with up to three substituents independently selected from the group 25 consisting of hydroxyl, halogen, (C1-C 4 )alkoxy, (C1-C 4 )-alkyl, halogenated (C1-C 4 )alkyl and halogenated (C1-C 4 )alkoxy. In a further embodiment of the present invention relates to compounds of formula 1, wherein R2 and R4 are independently selected from: 30 (a) an alkyl group selected from (i) -(C1-C 8 )alkyl, optionally substituted with substituents independently selected from the group consisting of hydroxyl, nitrile, -O-R '; -0-phenyl, -O-(C1-C 4 )alkyl phenyl, alkylamino, alkylamido, preferably carbamoyl, -S-R 7 ', and -(C=O)-OR 8 ', the number of substituents on said alkyl portion being up to five for hydroxyl and 35 one, two or three for any combination of said other substituents; (ii) -(C1-C 4 )alkyl, optionally substituted with one or two substituents independently se lected from the group consisting of aryl, heteroaryl, and cycloheteroalkyl, WO 2006/125800 PCT/EP2006/062587 27 wherein the aryl is preferably selected among phenyl, naphthyl, indanyl, indenyl, and 1,2,3,4-tetrahydro-naphthalen-1-yl, more preferably the aryl is phenyl or naphthyl, and which aryl is optionally substituted with halogen, hydroxyl, (C1-C 6 )alkoxy, (C1 5 C 6 )alkyl, halogenated (C1-C 4 )alkyl, halogenated (C1-C 4 )alkoxy, sulfamoyl, or alkylamide, preferably carbamoyl, the number of substituents on said aryl portion being up to three for halogen and one or two for any combination of said other substituents; or which aryl is optionally substituted by two groups which are attached to adjacent 10 carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms selected from N and 0, the number of N atoms being 0, 1, 2 or 3 and the number of 0 atoms being 0, 1 or 2, preferably a [1,3]-dioxol group; wherein the heteroaryl is preferably selected among pyrrolyl, thienyl, furyl, imida 15 zolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimid inyl, pyrazinyl, pyridazinyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran and benzo[b]thiophene, more preferably the heteroaryl is thienyl, furyl, imidazolyl, pyridinyl, indolyl, or benzoimidazolyl, and 20 which heteroaryl is optionally substituted with one or two, preferably one substitu ent independently selected from the group consisting of (C1-C 4 )alkoxy, pref erably methoxy, (C1-C 4 )alkyl, preferably methyl, and halogenated (C 1

-C

4

)

alkyl; wherein the cycloheteroalkyl group is preferably selected from the group consisting 25 of pyrrolidinyl, tetrahydrofuranyl, dihydro-1H-pyrrolyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, mor pholinyl, thiomorpholinyl, piperazinyl, 1,3-dihydro-benzoimidazolyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl, preferably the cycloheteroalkyl group is piperidinyl or morpholinyl; and 30 which cycloheteroalkyl is optionally substituted with up to three substituents inde pendently selected from the group consisting of oxo, hydroxyl, (C1-C 4 )-alkyl, phenyl, -(C1-C 4 )alkyl-phenyl, preferably benzyl, -(C=0)-0-(C1-C 4 )alkyl, and alkylamino, preferably the cycloheteroalkyl moiety is not substituted; (iii) -cyclo(C 3

-C

8 )alkyl, optionally substituted with hydroxyl; 35 (iv) -(C1-C 4 )alkyl-cyclo(C 3

-C

8 )alkyl, optionally substituted with hydroxyl; (v) a bicyclic ring system of 6 to 10 carbon atoms selected from the group consisting of Bicyclo[2.1.1]hexyl, Bicyclo[2.2.1]heptyl, Bicyclo[3.2.1]octyl, Bicyclo[2.2.2]octyl, Bicyclo[3.2.2]nonanyl, Bicyclo[3.3.1]nonanyl, and Bicyclo[3.3.2]decanyl; and (vi) a fused ring system of up to 10 carbon atoms, preferably adamantyl; WO 2006/125800 PCT/EP2006/062587 28 (b) aryl, wherein the aryl is preferably selected among phenyl, naphthyl, indanyl, indenyl, and 1,2,3,4-tetrahydro-naphthalen-1-yl, and which aryl is optionally substituted with substituents independently selected from the 5 group consisting of hydroxyl; halogen, preferably fluorine or chlorine; (C1

C

6 )alkoxy, preferably (C1-C 2 )alkoxy; (C1-C)alkyl, preferably (C1-C 4 )alkyl; halo genated (C1-C)alkyl, preferably halogenated (C1-C 4 )alkyl, more preferably trifluoromethyl; halogenated (C 1

-C

6 )alkoxy, preferably halogenated (C1-C 4 )alkoxy, more preferably trifluoromethoxy; -(C1-C 4 )alkyl-(C=O)-OR'; nitrile, nitro, sulfa 10 moyl, -(C=O)-R 8 ', -(C=O)-OR', -NH-(C=O)-R 8 ', -S-R', -SO 2

-R

8 ', alkylamino, alkylamido, preferably carbamoyl, phenyl, and a further heteroaryl group, optionally substituted with (C1-C 4 )alkyl, preferably 6-methyl-benzothiazolyl; the number of substituents on said aryl portion being up to three for halogen, and one or two for any combination of said other moieties; or 15 which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, op tionally containing up to three heteroatoms selected from N and 0, the number of N atoms being 0, 1, 2 or 3 and the number of 0 atoms being 0, 1 or 2, preferably a [1,3]-dioxol group; 20 (c) heteroaryl, wherein the heteroaryl is preferably selected among pyrrolyl, thienyl, furyl, imidazolyl, thi azolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, ben zofuran and benzo[b]thiophene; more preferably heteroaryl is furyl, thiazolyl, pyra 25 zolyl, pyridinyl, quinolinyl, or benzo[b]thiophene, and which heteroaryl is optionally substituted with up to three, preferably up to two substi tuents independently selected from the group consisting of halogen, (C1-C 4 )-alkyl, hydroxyl, halogenated (C1-C 4 )alkyl, -(C1-C 4 )alkoxy, -(C1-C 4 )alkyl-(C=0)-OR', O-Ar', -SO 2 -Ar", phenyl, -(C 1

-C

4 )alkyl-phenyl, nitrile, alkylamino, and alkylami 30 do, preferably carbamoyl; preferably selected from the group consisting of halogen, (C1-C 4 )alkyl, halogenated (C1-C 4 )alkyl, -(C 1

-C

4 )alkyl-(C=O)-OR 8 ', -0-Ar', -SO 2 Ar"and phenyl; or (d) cycloheteroalkyl, wherein the cycloheteroalkyl is preferably selected among pyrrolidinyl, tetrahydrofuranyl, 35 dihydro-1H-pyrrolyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidi nyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dihydro benzoimidazolyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl; more prefe rably cycloheteroalkyl is pyrrolidinyl, morpholinyl, tetrahydrofuranyl, piperidinyl or azepanyl, and WO 2006/125800 PCT/EP2006/062587 29 which cycloheteroalkyl is optionally substituted with up to three, preferably one or two substituents independently selected from the group consisting of oxo, (C1-C 4 )alkyl, phenyl, -(C1-C 4 )alkyl-phenyl, hydroxyl, (C1-C 4 )alkoxy, and -(C1-C 4 )alkyl-(C=O)

OR

8 '; preferably selected from the group consisting of oxo, (C1-C 4 )alkyl, preferably 5 methyl, and (C1-C 4 )alkyl-phenyl, preferably benzyl; wherein

R

7 ' represents (C1-C 4 )alkyl, preferably (C1-C 2 )alkyl, optionally substituted with one or two hy droxyl groups,

R

8 ' represents hydrogen, (C1-C 4 )alkyl, preferably methyl, or (C1-C 2 )alkyl-phenyl, preferably 10 benzyl; and Ar" represents phenyl optionally substituted with up to three halogen atoms; or wherein the ring or ringsystem formed by R 2 and R 4 together with the nitrogen atom, to which R 2 and R 4 are attached, is selected from the group consisting of -N -N o -N S -N N / o / S N -N -N-N -N 15 -N and -N wherein the ring or the ring-system is optionally substituted (i) with up to three substituents independently selected from the group consisting of (a) hydroxyl, (b) oxo, 20 (c) (C1-C 4 )-alkyl, optionally substituted with up to two hydroxyl and/or (C1-C 4 )-alkoxy groups, whereby the alkyl-chain of the (C1-C 4 )-alkoxy moiety may optionally be fur ther substituted with one or two, preferably one hydroxyl group; (d) cyclo(C 3

-C

8 )alkyl; (e) -(C=O)-O-(C1-C 4 )-alkyl; 25 (f) phenyl, optionally substituted with halogen, (C1-C 4 )-alkyl, preferably methyl, (C1

C

4 )-alkoxy, or halogenated (C1-C 4 )-alkyl, preferably halogenated methyl, the num ber of said substituents on the phenyl moiety being up to three for halogen, and one or two for any combination of said other substituents; (g) phenyl-(C1-C 4 )alkyl, preferably benzyl, optionally substituted in the phenyl group by 30 up three halogen, or optionally substituted in the phenyl group by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly WO 2006/125800 PCT/EP2006/062587 30 unsaturated cyclic 5 or 6-membered ring system, optionally containing up to two 0 atoms; (h) alkylamide, preferably carbamoyl; (i) heteroaryl, wherein the heteroaryl is preferably selected from the group consisting 5 of pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, benzoi midazolyl or benzo[b]thiophene, more preferably the heteroaryl is pyridinyl; and (j) cycloheteroalkyl, wherein the cycloheteroalkyl is preferably selected from the group consisting of pyrrolidinyl, 1,3-dihydro-benzoimidazolyl, morpholinyl, tetrahydrofura nyl, piperidinyl and azepanyl; more preferably the cycloheteroalkyl group is pyrroli 10 dinyl or 1,3-dihydro-benzoimidazolyl, which cycloheteroalkyl group is optionally substituted with oxo; or (ii) by two groups which are attached to the same carbon atom and are combined into a sa turated or partly unsaturated cyclic 5, 6, or 7-membered ring system, optionally containing up to three heteroatoms selected from N and 0, the number of N atoms being 0, 1, 2 or 3 15 and the number of 0 atoms being 0, 1 or 2, whereby the cyclic ring system may optionally be further substituted with up to two sub stituents independently selected from oxo and phenyl. In one embodiment, the invention relates to a compound of the following formula XLII 13 R12 R1 H Rii OI 20 R2 wherein Y represents -NR 4 -, -0-, a bond or -N H-N R 4 -, i.e. compounds of formula 1, wherein -X-A-Y- together represent a group selected from 25 (a) -CO-NR 4 -, (b) -CO-O-, (c) -CO-, and (d) -CO-NH-NR 4 -, the preferred meanings of R 1 , RIO, R", R 1 2 , R 1 3 and R 14 are as indicated above, and 30 n represents 0, 1, 2, 3, 4, or 5. In one embodiment, the invention relates to a compound of the following formula VI WO 2006/125800 PCT/EP2006/062587 31 13 R12 R14 H I RIO (VI) /N R4 R2 i.e. a compound of formula 1, wherein -X-A-Y- together represent -CO-NR 4 -, and wherein the preferred meanings of R 1 , RIO, R", R 1 2 , R 1 3 and R 14 are as indicated above, and n represents 0, 1, 2, 3, 4, or 5, preferably n represents 2, 3 or 4. 5 In this embodiment, R 2 preferably represents (i) -(C1-C 4 )alkyl, which is optionally substituted with one or two substituents independ ently selected from the group consisting of hydroxyl, halogen, and (C1-C 4 )alkoxy; (ii) -(C 3

-C

8 )cycloalkyl; 10 (iii) aryl or -(C1-C 4 )alkyl-aryl, wherein the aryl is phenyl or naphthyl, which phenyl is optionally substituted with one or two substituents independently se lected from the group consisting of hydroxyl, halogen, cyano, (C1-C 4 )alkoxy and halogenated (C1-C 4 )alkoxy; or which phenyl is optionally substituted by two groups which are attached to adjacent 15 carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 0 atoms; or (iv) heteroaryl or -(C1-C 4 )alkyl-heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, indazolyl, or benzoimidazolyl; which heteroaryl is optionally substituted with one or two substituents independently 20 selected from the group consisting of -(C1-C 4 )alkyl and -(C1-C 4 )alkyl-(C=O) O-(C1-C 4 )alkyl; and R 4 is independently selected from H or -(C1-C 4 )-alkyl or -(C1-C 4 )-alkyl-phenyl, wherein the phenyl group is optionally substituted with one or two (C1-C 4 )alkoxy groups; or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a ring, 25 which is selected from the group consisting of morpholine, piperidine, thiomorpholine and piperazine, wherein the ring is optionally substituted with a -(C1-C 4 )alkyl group. In this embodiment, R2 more preferably represents 30 (i) -(C1-C 4 )alkyl, which is optionally substituted with one or two (C1-C 4 )alkoxy groups; (ii) -(C 3

-C

8 )cycloalkyl; (iii) phenyl or -(C1-C 4 )alkyl-phenyl, WO 2006/125800 PCT/EP2006/062587 32 which phenyl is optionally substituted with one or two substituents independently se lected from hydroxyl, halogen, cyano and (C1-C 4 )alkoxy; or which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring 5 system, containing 1 or 2 0-atoms; or (iv) heteroaryl or -(C1-C 4 )alkyl-heteroaryl, wherein the heteroaryl is thiazolyl, pyridinyl, in dolyl, or indazolyl; which heteroaryl is optionally substituted with one or two -(C1-C 4 )alkyl groups; and R 4 is independently selected from -H, -(C1-C 4 )-alkyl or -(C1-C 4 )-alkyl-phenyl, wherein 10 the phenyl group is optionally substituted with one or two (C1-C 4 )alkoxy groups; or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a ring, which is selected from the group consisting of morpholine, piperidine, and piperazine, wherein the ring is optionally substituted with a -(C1-C 4 )alkyl group. 15 Mostly preferred are compounds according to general formula VI, wherein

R

2 represents a -(C1-C 4 )alkylphenyl, preferably a benzyl group, or a thiazolyl group, optionally sub stituted with -(C1-C 4 )-alkyl, preferably methyl, and R 4 represents -H; or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a morpholine group, and 20 n represents 2 or 3. In a further embodiment the invention relates to a compound of the following formula XL R13 R12 R14 HR1 R40 (XL) W, H H RO CN' Y R HYR 0 wherein Y represents -NH-, a bond, or -0-; i.e compounds of formula 1, wherein -X-A-Y 25 together represent -NH-CO-NH-, -NH-CO-0-, or -NH-CO-; the preferred meanings of R 1 , R 1 0 , R", R1 2 , R 1 3 and R 1 4 are as indicated above; and n represents 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4. A further embodiment of the invention relates to a compound of the following formula XVII, WO 2006/125800 PCT/EP2006/062587 33

R

13

R

1 2

R

14 H R 1 1 (XVII) R, H n H SN NR2 0 wherein the preferred meanings of R 1 , RI 0 , R", R 1 2 , R 13 and R 1 4 are as indicated above; and n preferably represents 1, 2, 3, or 4, even more preferably 3 or 4. 5 In this embodiment, R 2 preferably represents (i) -(C1-C 4 )alkyl, (ii) -(C 3

-C

8 )cycloalkyl, (iii) -(C1-C 4 )alkyl-(C 3

-C

8 )cycloalkyl, (iv) aryl, wherein the aryl is phenyl or naphthyl, 10 which phenyl is optionally substituted with one or two substituents independently se lected from the group consisting of hydroxyl, halogen, -CO-O(C1-C 4 )aky and (C1-C 4 )alkoxy; or which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring 15 system, containing 1 or 2 0 atoms, or (v) -(C1-C 4 )alkyl-phenyl. A further embodiment of the invention relates to a compound of the following formula XXIII, R13 R12 R11 14 H R1HRio (XXIII) O HNl R2 0 20 wherein the preferred meanings of R 1 , RI 0 , R", R 1 2 , R 13 and R 1 4 are as indicated above; and n preferably represents 1, 2, 3, or 4. In this embodiment, R 2 preferably represents (i) -(C1-C 4 )alkyl, 25 (ii) -(C 3

-C

8 )cycloalkyl, (iii) -(C1-C 4 )alkyl-(C 3

-C

8 )cycloalkyl, (iv) -(C1-C 4 )alkyl, substituted with one or two substituents independently selected from the group consisting of -O-(C1-C 4 )alkyl and -O-(C1-C 4 )alkyl-phenyl, (v) phenyl, WO 2006/125800 PCT/EP2006/062587 34 which phenyl is optionally substituted with one, two or three substituents independ ently selected from the group consisting of halogen and (C1-C 4 )alkoxy; (vi) -(C1-C 4 )alkyl-phenyl; or (vii) adamantly. 5 In another embodiment, the present invention relates to compounds of formula (1), wherein X-A-Y- together represent a group selected from -NH-SO 2 -NH-, -NH-SO 2 -O-, and -NH-SO 2 -, and n represents 1, 2, 3, or 4. 10 A further embodiment of the invention relates to a compound of the following formula XXIV, R13 R12 w e t e pR 1 1 R1 HRi0 (XXIV) O, Hn=1/O ISR2 0 wherein the preferred meanings of R1, R10, R", R 12, R 1 and R 14 are as indicated above; and n preferably represents 1, 2, 3, or 4. 15 In this embodiment, R 2 preferably represents (i) aryl, wherein the aryl is selected among phenyl and naphthyl, which aryl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, nitro, (C1-C 4 )alkoxy, and -(C1-C 4 )alkyl; or (ii) heteroaryl, wherein the heteroaryl is furyl, thienyl, or thiazolyl, or indolyl, 20 which heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of -S0 2 -phenyl and (C1-C 4 )alkyl. In another embodiment, the present invention relates to compounds of formula (1), wherein X-A-Y- together represent a group selected from -0-CO-NH-, -0-CO-, and -0-CO-NH-SO 2 25 NR 4 -, and n represents 1, 2, 3, 4, 5 or 6. A further embodiment of the invention relates to a compound of the following formula XXVI, R13 R12 R14 H

R

1 0 (XXVI) H H ( H O N-R2

O

WO 2006/125800 PCT/EP2006/062587 35 wherein the preferred meanings of R 1 , R 1 0 , R", R 1 2 , R 1 3 and R 14 are as indicated above; and n preferably represents 3, 4, 5 or 6. In this embodiment, R2 preferably represents phenyl or naphthyl, 5 which phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, nitro, -CO-O(C1-C 4 )alkyl and (C1-C 4 )alkoxy and halo genated (C1-C 4 )alkyl; or which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 0 10 atoms. A further embodiment of the invention relates to a compound of the following formula XXVIII, R13 R12 R14 H R11 H H = H1 0 (XXVIII) ROH /R2 O N-S-N II\R4 wherein the preferred meanings of R 1 , R 10 , R", R 1 2 , R 1 3 and R 14 are as indicated above; and n 15 preferably represents 3, 4, 5 or 6. In this embodiment, R 2 preferably represents (i) -(C1-C 4 )alkyl, (ii) -(C 3

-C

8 )cycloalkyl, 20 (iii) -(C1-C 4 )alkyl-phenyl, (iv) phenyl, or (v) heteroaryl or -(C1-C 4 )alkyl-heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indolyl, or benzoimidazolyl; and preferably R 4 is independently selected from H, -(C1-C 4 )-alkyl and -(C1-C 4 )alkyl-phenyl; or 25 R2 and R4 may form together with the nitrogen atom, to which R2 and R4 are attached, a ring, which is selected from the group consisting of morpholine, thiomorpholine and piperazyl, and which is optionally substituted with (C1-C 4 )-alkyl. A further embodiment of the invention relates to a compound of the following formula XXXI, WO 2006/125800 PCT/EP2006/062587 36 R13

R

1 2 R H n=1-6 0 OH wherein the preferred meanings of R 1 , R 1 0 , R", R 12 , R 13 and R 14 are as indicated above; and n represents 1, 2, 3, 4, 5 or 6, preferably 3 or 4. 5 Preferred embodiments of the invention relate to the following compounds: N-Benzyl-4-(2-ethyl-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide N-Benzyl-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide N-Benzyl-4-(3-hydroxy-2-(2-methoxy-ethyl)-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide N-Benzyl-4-(3-hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide 10 2-Ethyl-3-hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-2-propyl-estra-1,3,5(1 0)-trien-1 7-one 3-Hydroxy-2-(2-methoxy-ethyl)-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one 3-Hydroxy-2-methoxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one 4-(2-Ethyl-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl)-butyramide 15 4-(3-Hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl)-butyramide N-Benzo[1,3]dioxol-5-ylmethyl-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl) butyramide 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-pyridin-3-ylmethyl-butyramide 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyl] 20 butyramide 3-Hydroxy-1 5p-(4-oxo-4-piperidin-1 -yl-butyl)-2-propyl-estra-1,3,5(1 0)-trien-1 7-one N-Benzyl-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-methyl-butyramide N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N methyl-butyramide 25 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(1 H-indazol-6-yl)-butyramide 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(2-methoxy-ethyl)-butyramide N-(2,4-Difluoro-benzyl)-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide N-Cyclohexyl-4-(2-ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide N-Benzo[1,3]dioxol-5-ylmethyl-4-(2-ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl) 30 butyramide 4-(2-Ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyl] butyramide 2-Ethoxy-3-hydroxy-1 5a-(4-oxo-4-piperidin-1 -yl-butyl)-estra-1,3,5(1 0)-trien-1 7-one 4-(2-Ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-N-(1 H-indazol-6-yl)-butyramide WO 2006/125800 PCT/EP2006/062587 37 N-Cyclohexyl-4-(3-hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide N-Benzyl-4-(3-hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide 3-Hydroxy-2-methoxy-1 5a-(4-oxo-4-piperidin-1 -yl-butyl)-estra-1,3,5(1 0)-trien-1 7-one 4-(3-Hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-N-(1 H-indazol-6-yl)-butyramide 5 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-1 -morpholin-4-yl-butan-1 -one 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-1 -morpholin-4-yl-butan-1 -one 4-(17-Fluoro-3-hydroxy-estra-1,3,5(10),16-tetraen-1 5p-yl)-l -morpholin-4-yl-butan-1 -one 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl)-propionamide 4-(17-Difluoromethylene-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -morpholin-4-yl-butan-1 -one 10 N-Cyclohexyl-4-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide N-Benzyl-4-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yi)-butyramide 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-N-(3,4-dihydroxy-benzyl)-butyramide 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyl] butyramide 15 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-1 -piperidin-1 -yl-butan-1 -one 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-N methyl-butyramide N-Cyclopropyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propionamide N-Cyclohexyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propionamide 20 N-Benzo[1,3]dioxol-5-ylmethyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl) propionamide N-Benzyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propionamide 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(3,4-dihydroxy-benzyl)-propionamide 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(3,5-dimethoxy-benzyl)-propionamide 25 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyl] propionamide 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 50-yl)-1 -piperidin-1 -yl-propan-1 -one 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N, N-diethyl-propionamide 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-N 30 methyl-propionamide 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-pyrazole 3-Sulphamate-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one, 3-Sulphate-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one, or a physiologically acceptable salt thereof. 35 Pharmaceutically acceptable salts of the compounds of the invention as well as commonly used pro-drugs and active metabolites of these compounds are also within the scope of the inven tion.

WO 2006/125800 PCT/EP2006/062587 38 Additionally, the invention relates to a compound of the invention for use as a medicament. Furthermore, the invention relates to the use of an effective amount of a compound of the in vention for the treatment or prevention of a steroid hormone dependent disease or disorder in a 5 mammal, in particular a human. Preferably the steroid hormone dependent disease or disorder is an estradiol dependent disease or disorder. Alternatively, the steroid dependent disease or disor der is an androgen-dependent disease or disorder. In addition, the invention relates to the use of a compound of the invention for the manufac 10 ture of a medicament for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, in particular a human. Preferably the steroid hormone dependent disease or disorder is an estradiol dependent disease or disorder. Alternatively, the steroid dependent disease or disorder is an androgen-dependent disease or disorder. 15 In a further embodiment of the invention, the steroid hormone dependent disease or disorder requires the inhibition of a 17p-HSD enzyme, preferably the human 17p-HSD1 enzyme and/or the inhibition of a STS enzyme, preferably the human STS enzyme. Preferably, the steroid hormone dependent disease or disorder is mediated by the dual action of the 17p-HSD1 and the STS en zyme. 20 Furthermore, the invention also relates to a method of treating a mammal such as a human having a condition related to 17p-HSD1 activity and/or STS activity or which condition can be treated by inhibition of one or both of said enzymes, comprising administering to the mammal an amount of a compound of this invention, or a salt or a prodrug thereof, which amount is effective to 25 treat the condition. Administration of compounds of this invention in combination with other phar maceuticals used in treatment of the listed conditions is contemplated. The conditions to be treated include but are not limited to malign estradiol dependent dis ease or disorder such as breast cancer, ovarian cancer, uterine cancer, endometrial cancer, and 30 endometrial hyperplasia. Preferably, the malign disease or disorder is characterized by a detect able level of 17P-HSD1 and/or STS expression within a cancer tissue sample. A detectable level of 17p-HSD1 and/or STS expression means that a certain level of 17p-HSD1 and/or STS mRNA or of 17p-HSD1 and/or STS protein can be detected by conventional molecular biology methods such as hybridization, PCR reactions, Northern or Western Blotting etc. An alternative detection method for 35 17P-HSD1 and/or STS expression is the measurement of the corresponding enzyme activity. According to a further aspect of the invention, the estradiol dependent disease is breast can cer and the mammal is a human post-menopausal female.

WO 2006/125800 PCT/EP2006/062587 39 Furthermore, the conditions to be treated include but are not limited to benign estradiol de pendent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adeno myosis, dysmenorrhea, menorrhagia, metrorrhagia, and urinary dysfunction. 5 In a further embodiment, the invention relates to use of an effective amount of a compound of the invention for the treatment or prevention of one of the aforementioned benign gynaecological diseases or disorders in a mammal whereby the mammal is a human, preferably a female and most preferably a pre- or peri-menopausal female. 10 According to a further aspect of the present invention, the steroid hormone dependent dis ease or disorder is an androgen-dependent disease or disorder. Preferably, said androgen dependent disease or disorder is selected from the group consisting of acne, seborrhea, androge netic alopecia, hirsutism, and prostate cancer. 15 According to a further aspect of the invention, the steroid hormone dependent disease or disorder to be treated is an estrogen- or androgen dependent disease or disorder requiring the lowering of the endogeneous estrogen or androgen concentration in a generalized or tissue specific manner. 20 Therefore, further steroid-dependent diseases which may be treated with an effective amount of a compound of the invention are selected from the group consisting of prostadynia, be nign prostatic hyperplasia, urinary dysfunction, lower urinary tract syndrome, squamous cell carci noma, rheumatoid arthritis, type I and 11 diabetes, systemic lupus erythematosus, multiple sclerosis, 25 myastenia gravis, thyroiditis, vasculitis, ulcerative colitis, Crohn's disease, psoriasis, contact derma titis, graft versus host disease, eczema, asthma, organ rejection following transplantation, colon cancer, tissue wounds, skin wrinkles and cataracts. According to a further embodiment, a compound of the present invention may be used for 30 the enhancement of cognitive function, i.e. in the treatment or prevention of cognitive dysfunctions, such as senile dementia, including Alzheimer's disease, by increasing the DHEAS levels in the central nervous system. The disclosed compounds are also useful as diagnostic agents (e.g. in diagnostic kits or for 35 use in clinical laboratories) for screening for the presence or absence of 17p-HSD1 and/or STS en zyme activity.

WO 2006/125800 PCT/EP2006/062587 40 SOME ADVANTAGES One key advantage of the present invention is that the compounds of the present invention can act as selective 173-HSD1 inhibitors and optionally additionally as STS inhibitors. Another ad 5 vantage of the compounds of the present invention is that they may be potent in vivo and suited for the therapeutic use in mammals, especially humans. Some of the compounds of the present inven tion may be non-estrogenic compounds. Here, the term "non-estrogenic" means exhibiting no or substantially no estrogenic activity on the estrogen receptor. Another advantage is that some of the compounds may not be capable of being metabolised to compounds which display or induce hor 10 monal activity. Some of the compounds of the present invention are also advantageous in that they may be orally active. DETAILED DESCRIPTION OF THE INVENTION 15 Definitions: The following terms are used to describe the present invention and in particular, to describe various constituents of the chemical composition useful in this invention. The terms are defined as follows: 20 As used herein, the terms "comprising" and "including" are used herein in their open, non limiting sense. The word "compound" shall here be understood to cover any and all isomers (e. g., 25 enantiomers, stereoisomers, diastereomers, rotomers, tautomers) or any mixture of isomers, prodrugs, and any pharmaceutically acceptable salt of said compound, unless the formula depicting the compound explicitly shows a particular stereochemistry. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a 30 single compound, salt, or the like. The term "17p-hydroxysteroid dehydrogenase type I" or "17p-HSD1" for short is used for the enzyme EC 1.1.1.62 and reduces estrone (El) to the biologically active estrogen, estradiol (E2). 35 The term "Steroid Sulphatase" or "STS" for short is used for the enzyme EC 3.1.6.2 and hydrolyses several sulphate steroids, such as estrone sulphate, dehydroepiandrosterone sulphate and cholesterol sulphate.

WO 2006/125800 PCT/EP2006/062587 41 The terms "inhibit" and "inhibition" include the meaning of to reduce and/or eliminate and/or mask and/or prevent a certain enzyme action. The term "17p-HSD1 inhibitor" as used herein with respect to the compound of the present 5 invention means a compound that can inhibit 17p-HSD1 activity, such as to reduce and/or eliminate and/or mask and/or prevent the action of 17p-HSD1. The 17p-HSD1 inhibitor may act as an reversible or irreversible inhibitor of 17p-HSD1. The ability of compounds to inhibit 17p-HSD1 activity can be assessed using cell lines recombinantly expressing the human 17p-HSD1 enzyme. Details on a suitable Assay Protocol are presented in the Examples section. It is to be noted that 10 the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit 17P-HSD1 activity; in particular a 17P-HSD1 inhibitor may have antagonistic activity towards the nuclear estrogen receptor. The term "STS inhibitor" as used herein with respect to the compound of the present 15 invention means a compound that can inhibit STS activity, such as to reduce and/or eliminate and/or mask and/or prevent the action of STS. The STS inhibitor may act as an antagonist. The ability of compounds to inhibit estrone sulphate activity can be assessed using either intact MCF-7 breast cancer cells or placenta microsomes. In addition, an animal model may be used. Details on suitable Assay Protocols are presented in following sections. It is to be noted that other assays 20 could be used to determine STS activity and thus STS inhibition. For example, reference may also be made to the teachings of international patent application WO 99/50453. Preferably, for some applications, a "STS inhibitor" is further characterized by the feature that if the sulphamate group were to be substituted by a sulphate group to form a sulphate derivative, then the sulphate derivative would be hydrolysable by an enzyme having steroid sulphatase (EC 3.1.6.2) activity, i.e. 25 when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37*C. In one preferred embodiment, if the sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sutphatase (EC 3.1.6.2) activity and would yield a Km value of less than 200 mM, preferably less than 150 mM, preferably less than 100 mM, preferably less than 75 mM, preferably 30 less than 50 mM, when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37*C. In one preferred embodiment, if the sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sutphatase (EC 3.1.6.2) activity and would yield a Km value of less than 200 pM, preferably less than 150 pM, preferably less than 100 pM, preferably less than 35 75 pM, preferably less than 50 pM, when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37*C. In a preferred embodiment, the compound of the present invention is not hydrolysable by an enzyme having steroid sulphatase (EC 3.1.6.2) activity. It is to be noted that the compound of WO 2006/125800 PCT/EP2006/062587 42 the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit STS activity. The terms "selective" and "selectivity" as used herein with respect to the compounds of the 5 present invention means a compound that can inhibit 17p-HSD1 and/or STS activity, and shows a higher inhibition value for these particular targets than with regard to other enzyme targets, in particular with regard to the 17p-HSD1 enzyme, and that has weak or no affinity for nuclear receptors, in particular that has weak or no affinity for the ER. Preferably a compound of the present invention has at least about a 100fold selectivity to a desired target (e.g. 17p-HSD1 or 10 STS), preferably at least about a 150fold selectivity to the desired target, preferably at least about a 200fold selectivity to the desired target, preferably at least about a 250fold selectivity to the desired target, preferably at least about a 300fold selectivity to the desired target, preferably at least about a 350fold selectivity to the desired target. 15 The term "substituted" means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or 20 more substituents. Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration preferably in the (R)- or (S)-configuration, whichever is most active, unless the stereochemistry is explicitly depicted in the corresponding compound formula. Substituents at a double bond or a ring 25 may be present in cis- (.=Z-) or trans (=E-) form, unless the stereochemistry is explicitly depicted in the corresponding compound formula. The compounds of formula (1) have a defined stereochemistry within the steroidal core structure according to the natural configuration for estrogenic steroids such as estradiol: H 30 The stereochemistry within the steroidal core structure is always shown in the corresponding compound formula and should not vary within the scope of the present invention, whereas the stereochemistry at the carbon atoms in the steroidal core carrying additional side chains and the stereochemistry of any asymmetric carbon atom within the side chains themselves is not fixed.

WO 2006/125800 PCT/EP2006/062587 43 Therefore, the term "compounds of formula (1)" or "compouns of formula (11)" etc also comprises the stereoisomers of the depicted compounds, unless a particular stereochemistry is explicitly shown within the formula. The stereochemistry shown in the respective formula prevails over the general term "stereoisomers". 5 The compounds of the formula I contain at least one additional chiral carbon atom, namely the carbon atom carrying the side chain in the 15-position of the steroide structure. The compounds can thus be present at least in two optically active stereoisomeric forms or as a racemate. The present invention includes both the racemic mixtures and the isomerically pure compounds of the 10 formula 1. The position of the substituents within the C15 position is characterized by a or P. A C15a derivative according to the present invention is represented by a compound of the following formula (II) R13 R12 R 14 H R 1 0 11 H H ) R(IIn O, A ' R2 whereas a C1 5P derivative according to the present invention is represented by a compound 15 of the following formula (111) R13 R12 R11 O y A Y R2 The compounds of the present invention may contain further asymmetric centers on the molecule, depending upon the nature of the various substituents. In certain instances, asymmetry 20 may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention, unless a particular stereochemistry is explicitly depicted in 25 the formula representing a respective compound. The term "halogen" refers to fluorine (F, Fluoro-), bromine (Br, Bromo-), chlorine (Cl, Chloro), and iodine (J, lodo-) atoms.

WO 2006/125800 PCT/EP2006/062587 44 The terms "dihalogen", "trihalogen" and "Perhalogen" refer to two, three and four substitu ents, respectively, each individually selected from the group consisting of fluorine, bromine, chlo rine, and iodine atoms. 5 The term "hydroxyl" refers to the group -OH The term "oxo" refers to the group =0 10 The term "carbamovl" refers to the group -CO-NH 2 The term "thio" refers to the group =S The term "thiol" refers to the group -SH 15 The term "sulfanyl" refers to the group -S The term "sulfoxy" or "sulfonyl" refers to the group -SO 2 20 The term "sulfamoyl" refers to the group -SO 2

-NH

2 The term "nitro" refers to the group -NO 2 The term "nitrile" or "cyano" refers to the group -CN 25 The term "oxime" refers to the group =N-0-Alkyl or =N-OH. For the purpose of the present invention, the carbon content of various hydrocarbon contain ing moieties is indicated by a prefix designating the minimum and maximum number of carbon at 30 oms in the moiety, i.e., the prefix C-Cj defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive. Thus C1-C 4 -alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof. The term "isyl" stands for a hydrocarbon radical which may be linear, cyclic or branched, 35 with single or multiple branching, whereby the alkyl group comprises 1 to 12 carbon atoms. In one embodiment, the term "alkyl" stands for a linear or branched (with single or multiple branching) al kyl chain of 1 to 8 carbon atoms, exemplified by the term (C1-C 8 )alkyl, more preferably of 1 to 6 carbon atoms exemplified by the term (C1-C 6 )alkyl. The term (C1-C 8 )alkyl is further exemplified by such groups as methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl; tert-butyl; n-pentyl; WO 2006/125800 PCT/EP2006/062587 45 isopentyl; neopentyl; tert-pentyl; 2- or 3-methylpentyl; n-hexyl; isohexyl, heptyl, octyl and the like. The alkyl or (C1-C 8 )alkyl group may be partially unsaturated, forming such groups as, for example, vinyl, propenyl (allyl), butenyl, pentenyl, pentinyl, hexenyl, octadienyl, and the like. The term "alkyl" further comprises cycloalkyl groups, preferably cyclo(C 3

-C

8 )alkyl which refers to cyclopropyl, 5 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof such as me thylcyclopropyl; 2- or 3-methylcyclobutyl; 2-, or 3-methylcyclopentyl, and the like. The cycloalkyl group may also be partly unsaturated, forming such groups as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl, and the like. Furthermore, the term "alkyl" comprises a cycloalkyl alkyl group comprising 4 to 12 carbon atoms, preferably "-(C1-C 4 )alkyl-cyclo(C 3

-C

8 )alkyl" which re 10 fers to a alkyl group of 1 to 4 carbon atoms as described above substituted with a cyclo(C 3

-C

8 )alkyl group as described above, forming such groups as for example cyclopropylmethyl, cyclohexyl methyl, cyclopentylethyl or cyclohexenylethyl. The term "alkyl" further comprises bicyclic ring sys tems of 6 to 10 carbon atoms, preferably Bicyclo[2.1.1]hexyl, Bicyclo[2.2.1]heptyl, Bicy clo[3.2.1 ]octyl, Bicyclo[2.2.2]octyl, Bicyclo[3.2.2]nonanyl, Bicyclo[3.3.1 ]nonanyl, Bicy 15 clo[3.3.2]decanyl; and the like, preferably Bicyclo[2.2.1]heptyl, and fused ring systems of up to 10 carbon atoms such as adamantyl and the like. The alkyl group may optionally be substituted by up to five, more preferably by up to three substituents independently selected from the group consisting of halogen, hydroxyl, optionally sub 20 stituted aryl, optionally substituted heteroaryl, optionally substituted cycloheteroalkyl, thiol, nitro, ni trile, alkoxy, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sul fonamide, acyl, carboxyl, and acylamino, as defined herein. These groups may be attached to any carbon atom of the alkyl moiety. 25 The alkyl group substituted with up to three independently selected aryl preferably refers to "aryl-(C1-C 4 )-alkyl" or "diaryl-(C1-C 4 )-alkyl", wherein the aryl is phenyl, naphthyl, indanyl, indenyl, or 1,2,3,4-tetrahydro-naphthalen-1-yl, preferably aryl is phenyl or naphthyl, forming such groups as for example benzyl, diphenylmethyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, naphthyl methyl or naphthylethyl. The alkyl chain may be further substituted as defined above; for example 30 the alkyl chain may carry an additional hydroxyl group. Furthermore, the alkyl chain may be par tially unsaturated, such as a vinyl group. The aryl moiety may optionally be substituted as defined herein. The alkyl group substituted with up to three independently selected heteroaryl group pref 35 erably refers to "heteroaryl-(C1-C 4 )-alkyl", wherein the heteroaryl is pyrrolyl, thienyl, furyl, imida zolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran, benzo[b]thiophene, preferably heteroaryl is furyl, indolyl, benzoimidazolyl, pyridinyl, thienyl or imidazolyl, forming such groups as for example benzoimidazolylmethyl, pyridinylmethyl, thienylmethyl, furylmethyl, indolylethyl, thienylethyl, WO 2006/125800 PCT/EP2006/062587 46 pyridinylethyl, or imidazolylpropyl. The heteroaryl moiety may optionally be substituted as defined herein. The alkyl group substituted with up to three independently selected cycloheteroalkyl groups 5 preferably refers to "cycloheteroalkyl-(C1-C 4 )-alkyl", wherein the cycloheteroalkyl is pyrrolidinyl, tet rahydrofuryl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl or thiazepanyl, preferably cycloheteroalkyl is piperidinyl, pyrrolidinyl, or morpholinyl, forming such groups as for example morpholinylethyl, morpholinylpropyl, piperid inylethyl or pyrrolidinylethyl. The cycloheteroalkyl moiety may optionally be substituted as defined 10 herein. The term "alkoxy" refers to a group -OR, where R may be alkyl (wherein the alkyl chain may be optionally further substituted as defined herein). Preferably, the term "alkoxy" refers to -O-(C1

C

6 )alkyl (or (C1-C 6 )alkoxy), with the (C1-C)alkyl group as defined above and optionally substituted 15 with up to three hydroxyl groups. The term "arvloxv' refers to a group -OAr, where Ar represents aryl as defined herein, which is optionally substituted in the aryl group with up to five independently selected substituents as de fined herein, in particular hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C 1

-C

4

)

20 alkyl, or halogenated (C1-C 4 )-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, aryloxy refers to phenoxy, optionally substituted as defined above. The term "arvlalkyloxy" refers to a group -O-(C1-C 4 )alkyl-Ar, where Ar represents aryl, which 25 is optionally substituted in the aryl group with up to five independently selected substituents as de fined herein, in particular hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C 1

-C

4

)

alkyl, or halogenated (C1-C 4 )-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, arylalkyloxy refers to benzyloxy, optionally substituted as defined above. 30 The term "acyL" refers to a group -(C=O)-R, where R may be hydrogen, optionally substi tuted alkyl, optionally substituted aryl or aryl-(C1-C 4 )-alkyl, optionally substituted heteroaryl or het eroaryl-(C1-C 4 )-alkyl, as defined herein. Preferably, the term "acyl" refers to a group -(C=O)-R', where R' represents hydrogen, (C1-C 4 )alkyl, phenyl, or phenyl-(C1-C 4 )alkyl, preferably benzyl, or 35 heteroaryl-(C1-C 4 )alkyl, preferably indolyl-methyl; whereby the phenyl moiety may be optionally substituted with independently selected substituents, especially hydroxyl, halogen, (C1-C 4 )alkoxy, (C1-C 4 )-alkyl or halogenated (C1-C 4 )alkyl, the number of said substituents being up to five for halo gen, and up to three for any combination of said other substituents.

WO 2006/125800 PCT/EP2006/062587 47 The term "carbonyl" represents a preferred selection of the term "acyl" and refers to the group -CHO. The term "alkylacyl" represents a preferred selection of the term "acyl" and refers to a group 5 -(C=O)-alkyl, preferably -(C=O)-(C1-C 4 )alkyl. The term carboxyll" refers to a group -(C=O)-OR, wherein R may be hydrogen, optionally substituted alkyl (preferably substituted with hydroxyl, halogen or (C1-C 4 )-alkoxy), optionally substi tuted aryl or aryl-(C1-C 4 )-alkyl, or optionally substituted heteroaryl or heteroaryl-(C1-C 4 )-alkyl, each 10 as defined herein. Preferably, the term carboxyll" refers to a group -(C=O)-OR', where R' repre sents hydrogen, (C1-C 4 )alkyl, phenyl, or phenyl-(C1-C 4 )alkyl, preferably benzyl; whereby the phenyl moiety may be optionally substituted with substituents independently selected from the group con sisting of hydroxyl, halogen, (C1-C 4 )alkoxy, (C1-C 4 )-alkyl, halogenated (C1-C 4 )alkyl and halogenated (C1-C 4 )alkoxy, the number of said substituents being up to five for halogen, and up to three for any 15 combination of said other substituents. The terms "carboxyl-(Cj-C 6 )alkyl" and "carboxyl-(Cj-C 4 )alkyl" refer to groups -(C1-C 6 )alkyl (C=0)-OR and -(C1-C 4 )alkyl-(C=O)-OR, respectively, which refer to an alkyl group of 1 to 6 and 1 to 4 carbon atoms, respectively, as described above, substituted with a -(C=O)-OR group as de 20 scribed above. Preferably the carboxyl group refers to -(C=O)-OR', wherein R' represents hydro gen, (C1-C 4 )alkyl, phenyl, or (C1-C 4 )alkyl-phenyl, preferably benzyl. Preferred examples of such carboxyl-(C1-C 6 )alkyl groups include acetic acid methyl ester, acetic acid ethyl ester, propionic acid benzyl ester, propionic acid ethyl ester, butyric acid methyl ester, and 3-methyl-butyric acid methyl ester. 25 The term "amino" refers to the group -NRR', where R and R' may independently be hydro gen, optionally substituted alkyl (preferred substituents comprise hydroxyl, halogen or (C 1

-C

4

)

alkoxy), optionally substituted aryl or aryl-(C1-C 4 )-alkyl, or optionally substituted heteroaryl or het eroaryl-(C1-C 4 )-alkyl, each as defined herein. 30 The term "alkylamino" represents a preferred selection of the term "amino" and refers to the group -NRR', where R and R' may independently be hydrogen or (C1-C 4 )alkyl. The term "alkylthio" or "alkylsulfanyl" refers to a group -SR, where R represents optionally 35 substituted alkyl (preferred substituents comprise hydroxyl, (C1-C 4 )-alkoxy or halogen), as defined herein; preferably R represents (C1-C 6 )alkyl, in particular (C1-C 4 )alkyl. The term "arylthio" or "arylsulfanyl" refers to a group -S-Ar, where Ar represents optionally substituted aryl (preferred substituents comprise hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, WO 2006/125800 PCT/EP2006/062587 48 halogenated (C1-C 4 )-alkyl, or halogenated (C1-C 4 )-alkoxy), as defined herein. Preferably, arylthio refers to optionally substituted phenylsulfanyl. The term "arylalkylthio" or "arylalkylsulfanyl" refers to a group -S-(C1-C 4 )alkyl-Ar, where Ar 5 represents optionally substituted aryl (preferred substituents comprise hydroxyl, halogen, (C 1

-C

4

)

alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, or halogenated (C1-C 4 )-alkoxy), as defined herein. Preferably, arylalkylthio refers to optionally substituted benzylsulfanyl. The term "alkylsulfonyl" refers to a group -S0 2 -R, where R represents optionally substituted 10 alkyl (preferred substituents comprise hydroxyl, (C1-C 4 )-alkoxy or halogen), as defined herein; pref erably R represents (C1-Ce)alkyl, in particular (C1-C 4 )alkyl. The term "arylsulfonvl" refers to a group -S0 2 -Ar, where Ar represents optionally substituted aryl (preferred substituents comprise hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated 15 (C1-C 4 )-alkyl, or halogenated (C1-C 4 )-alkoxy), as defined herein. Preferably, arylsulfonyl refers to optionally substituted benzenesulfonyl. The term "arylalkylsulfonyl" refers to a group -S0 2 -(C1-C 4 )alkyl-Ar, where Ar represents op tionally substituted aryl (preferred substituents comprise hydroxyl, halogen, (C1-C 4 )-alkyl, (C 1

-C

4

)

20 alkoxy, halogenated (C1-C 4 )-alkyl, or halogenated (C1-C 4 )-alkoxy), as defined herein. Preferably, arylalkylsulfonyl refers to optionally substituted benzylsulfonyl. The term "amido" refers to the group -(C=O)-NRR', where R and R' may independently be hydrogen, optionally substituted alkyl (preferred substituents comprise hydroxyl, halogen or (C1 25 C 4 )-alkoxy), optionally substituted aryl or aryl-(C1-C 4 )-alkyl ((preferred substituents comprise hy droxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, or halogenated (C 1

-C

4

)

alkoxy), or optionally substituted heteroaryl or heteroaryl-(C1-C 4 )-alkyl, as defined herein. The term "alkylamido" represents a preferred selection of the term "amido" and refers to the 30 group -(C=O)-NRR', where R and R' may be independently selected from hydrogen or (C1

C

4 )alkyl. The term "acylamino" refers to the group -NR-CO-R', where R and R' may independently be hydrogen, optionally substituted alkyl (preferred substituents comprise hydroxyl, halogen or (C1 35 C 4 )-alkoxy), optionally substituted aryl or aryl-(C1-C 4 )-alkyl (preferred substituents comprise hy droxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, or halogenated (C 1

-C

4

)

alkoxy), optionally substituted heteroaryl or heteroaryl-(C1-C 4 )-alkyl, as defined herein. Preferably, acylamino refers to -NH-CO-(C1-C 4 )-alkyl.

WO 2006/125800 PCT/EP2006/062587 49 The term "carbonylamino" represents a preferred selection of the term "acylamino" and re fers to the group -NR-CO-CH 2 -R', where R and R' may be independently selected from hydrogen or (C1-C 4 )alkyl. 5 The term "sulfonamide" refers to the group -SO 2 -NRR', wherein R and R' may independ ently be selected from hydrogen or (C1-C 4 )alkyl. Halogenated alkyl, halogenated alkoxy and halogenated alkylthio are substituents in which the alkyl moieties (preferably (C1-C)alkyl, more preferred (C1-C 4 )alkyl, and most preferred methyl) 10 are substituted either partially or in full with halogens, generally with chlorine and/or fluorine. Pre ferred examples of such substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthio, di chloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoromethyl. The term "cycloheteroalkyl" refers to a four- to eight-membered heterocyclic ring containing 15 at least one heteroatom, such as N, 0 or S, the number of N atoms being 0-3 and the number of 0 and S atoms each being 0-1, which system may be saturated, partly unsaturated or hydroaromatic, and which ring can be part of a multiple condensed ring-system in which some rings may be aro matic. Examples of such cycloheteroalkyls include pyrrolidinyl, tetrahydrofuryl, tetrahydrothio phenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomor 20 pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, 3,6 dihydro-2H-pyridinyl, 1,3-dihydro-benzoimidazolyl and the like. Preferred examples of such cyclo heteroalkyl groups are pyrrolidinyl, morpholinyl, tetrahydrofuryl, piperidinyl or azepanyl. The cycloheteroalkyl group may optionally be substituted by up to three substituents, inde 25 pendently selected from the group consisting of oxo, alkyl, optionally substituted aryl or aryl-(C1

C

4 )-alkyl, hydroxyl, (C1-C 6 )alkoxy, halogenated (C1-C)alkyl, halogenated (C1-C 6 )alkoxy, carboxyl (C1-C)alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, (C1-C)alkylthio, arylthio or arylalkylthio, amino, amido, acyl, and acylamino, as defined herein. The substituents of the cycloheteroalkyl groups may be attached to any carbon atom of the cycloheteroalkyl moiety. 30 Substituted cycloheteroalkyl is preferably substituted with oxo, (C1-C 4 )alkyl, preferably methyl, phenyl and/or phenyl-(C1-C 4 )alkyl, in particular benzyl. The terms "a~y" or "Ar" refer to an aromatic carbocyclic group comprising 6 to 14, more pref erably 6 to 10, carbon atoms and having at least one aromatic ring or multiple condensed rings in 35 which at least one ring is aromatic. Preferably, aryl is phenyl, naphthyl, indanyl, indenyl, or 1,2,3,4 tetrahydro-naphthalen-1 -yl. The term "heteroaryl" refers to an aromatic carbocyclic group of having a single 4 to 8 mem bered ring or multiple condensed rings comprising 6 to 14, more preferably 6 to 10, ring atoms and WO 2006/125800 PCT/EP2006/062587 50 containing at least one heteroatom, such as N, 0 or S, within at least one ring, the number of N at oms being 0-3 and the number of 0 and S atoms each being 0-1; in which group at least one het erocyclic ring is aromatic. Examples of such groups include pyrrolyl, thienyl, furyl, imidazolyl, thia zolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indo 5 lyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoimidazolyl, 1,3-dihydro-benzoimidazolyl, benzofu ran, benzo[b]thiophene and the like. Preferably, heteroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo[b]thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl. The aryl and the heteroaryl group may optionally be substituted by substituents independ 10 ently selected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C)alkyl, halo genated (C1-Ce)alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C1-C)alkyl, oxo, thiol, nitro, nitrile, sul famoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, (C1-C 6 )alkylthio, arylthio or arylalkylthio, al kylsulfonyl, arylsulfonyl, amino, amido, acyl, and acylamino, as defined herein, the number of said substituents being up to five for halogen, and up to three for any combination of said other sub 15 stituents; whereby the aryloxy, arylalkyloxy, arylthio or arylalkylthio group may be further optionally substituted in the aryl moiety with independently selected substituents as defined herein. The het eroaryl group may further be optionally substituted with an aryl group, which may be optionally substituted in the aryl moiety with independently selected substituents as defined herein. The aryl group may further be optionally substituted with a heteroaryl group or a second aryl group. 20 The aryl may be further substituted by two groups which are attached to adjacent carbon at oms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, 0 or S, the number of N atoms being 0-3 and the number of 0 and S atoms each being 0-2. Preferably, the two groups which are 25 attached to adjacent carbon atoms, are combined into a saturated cyclic 5 or 6 membered ring sys tem, optionally containing up to three heteroatoms, such as N or 0, the number of N atoms being 0-3 and the number of 0 atoms each being 0-2. This cyclic ring system may optionally be further substituted by an oxo group. Preferred examples of such a substituted aryl groups are benzo[1,3]dioxol and 1,3-dihydro-benzoimidazol-2-one. 30 The statement is made that when two side chains are found on a single N, they can be com bined, including the N to which they are attached, into a heterocyclic ring of 4-, 5-, 6-, 7- or 8 at oms, which can be saturated, partly unsaturated or aromatic, which can optionally contain up to three additional heteroatoms selected from N, 0 or S, the number of N atoms being 0-3 and the 35 number of 0 and S atoms each being 0-2; and which ring can be part of a multiple condensed ring system, in which some rings may be aromatic. Preferred examples of such heterocyclic ring sys tems, including the N, to which the respective side chains are attached, comprise: WO 2006/125800 PCT/EP2006/062587 51 -N -N 0 -N S N N -N O S N _N N NN / N / s N N N NQN N N The aforementioned heterocyclic ring system can be optionally substituted by up to three substituents, which can be attached to any carbon or nitrogen atom of the heterocyclic ring system. 5 Preferred examples of substituted heterocyclic ring systems are: R R -N -N -N N-R R R N-R -N -N -N The optional up to three independently selected substituents for the heterocyclic ring system may be chosen among optionally substituted alkyl, halogen, hydroxyl, oxo, thiol, nitro, nitrile, (C1 C)-alkoxy, aryl, heteroaryl, optionally substituted cycloheteroalkyl, aryloxy, arylalkyloxy, amino, 10 amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyl, and acylamino, as defined herein, whereby all aryl or heteroaryl moieties may be optionally substituted with up to five, preferably up to three independently selected substituents as defined herein. Furthermore, the aforementioned heterocyclic ring system may be substituted by two groups 15 which are attached to the same carbon atom and are combined into a saturated or partly unsatu rated cyclic 4, 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, 0 or S, the number of N atoms being 0-3 and the number of 0 and S atoms each being 0-2. This cyclic ring system may optionally be further substituted by up to three substitutents inde pendently selected from oxo, (C1-C)-alkyl, aryl, preferably phenyl, and aryl-(C1-C 4 )-alkyl, preferably 20 benzyl. Preferred examples of such substituted heterocyclic ring systems are 1,4-dioxa-8-aza spiro[4.5]decane, 1,3,8-triaza-spiro[4.5]decane, 1,3,8-triaza-spiro[4.5]decan-4-one, 1-Phenyl-1,3,8 triaza-spiro[4.5]decane, and 1-Phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

WO 2006/125800 PCT/EP2006/062587 52 The term "sulphamate group" as used herein, refers to a group -O-SO 2

-NR

3

R

3 ', and in cludes a steroidal ester of sulphamic acid or a steroidal ester of an N-substituted derivative of sul phamic acid, or a salt thereof. If -O-R 1 is a sulphamate group then the compound of the present in vention is referred to as a sulphamate compound. 5 The term "carbamate group" as used herein, refers to a group -O-CO-NR 3

R

3 ', and includes a steroidal ester of carbamic acid or a steroidal ester of an N-substituted derivative of carbamic acid, or a salt thereof. If -O-R 1 is a carbamate group then the compound of the present invention is referred to as a carbamate compound. 10 The term "Phosphonate group" as used herein, refers to a group -O-PO(OR 6

)-R

3 , and in cludes a steroidal ester of phosphonic acid or a steroidal ester of an O-substituted derivative of phosphonic acid, or a salt thereof. If -O-R 1 is a phosphonate group then the compound of the pre sent invention is referred to as a phosphonate compound. 15 The term "thiophosphonate group" as used herein, refers to a group -O-PS(OR 6

)-R

3 , and includes a steroidal ester of thiophosphonic acid or a steroidal ester of an O-substituted derivative of thiophosphonic acid, or a salt thereof. If -O-R 1 is a thiophosphonate group then the compound of the present invention is referred to as a thiophosphonate compound. 20 The term "Dhosphate group" as used herein, refers to a group -O-PO(OR' 6

)-OR

3 , and in cludes a steroidal ester of phosphoric acid or a steroidal ester of an O-substituted derivative of phosphoric acid, or a salt thereof. If -O-R 1 is a phosphate group then the compound of the present invention is referred to as a phosphate compound. 25 The term "sulphonate group" as used herein, refers to a group -O-SO 2

-R

3 , and includes a steroidal ester of sulphonic acid, or a salt thereof. If -O-R 1 is a sulphonate group then the com pound of the present invention is referred to as a sulphonate compound. 30 The term "sulphate group" as used herein, refers to a group -O-SO 2

-OR

3 , and includes a steroidal ester of sulphuric acid, or a salt thereof. If -O-R 1 is a sulphate group then the compound of the present invention is referred to as a sulphate compound. For all above-mentioned sulphamate-, carbamate-, phosponate-, thiophosphonate-, phos 35 phate-, sulphonate-, and sulphate- groups, the substituents R 3 and R 3 ', if present, are independ ently selected from H, alkyl, aryl and arylalkyl, as defined herein, or form together with the nitrogen atom, to which R 3 and R3' are attached, a heterocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three addi tional heteroatoms selected from N, 0 or S, the number of additional N atoms being 0, 1, 2 or 3 WO 2006/125800 PCT/EP2006/062587 53 and the number of 0 and S atoms each being 0, 1 or 2. Preferably, at least one of R9 and R10 is H, and even more preferred, each of R 9 and R 10 is H. If the substituent R 1 6 is present in one of the aforementioned groups, then represents -H, alkyl, or arylalky, as defined herein above. Preferably,

R

16 represents -H. 5 The term "Prodrua" as used herein, represents derivatives of the compounds of the invention that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process. In particular, pro-drugs are derivatives of the compounds of the invention in which functional groups carry additional substituents which may be cleaved under 10 physiological conditions in vivo and thereby releasing the active principle of the compound (e. g., a pro-drug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form). The term "Pharmaceutically acceptable salts" refers to salt forms that are pharmacologically 15 acceptable and substantially non-toxic to the subject being administered the compounds of the in vention. Pharmaceutically acceptable salts of compounds of formula I include conventional and stoichiometrical acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Acid addition salts, for example, from compounds of formula I with a basic nitrogen atom are formed preferably with organic or inorganic acids. Suitable inorganic 20 acids are, for example, halogenic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, or sulfonic acids, for example ace tic acid, propionic acid, glycolic acid, lactic acid, hydroxybutyric acid, malic acid, malenic acid, malonic acid, salicylic acid, fumaric acid, succinic acid, adipic acid, tartaric acid, citric acid, glutaric acid, 2- or 3-glycerophosphoric acid and other mineral and carboxylic acids well known to those 25 skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. Compounds containing acidic substituents may also form salts with inorganic or organic bases. Examples of suitable bases for salt formation include, but are not limited to, inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from am 30 monium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hy droxide). Also contemplated are salts formed with pharmaceutical acceptable amines such as am monia, alkyl amines, hydroxyalkylamines, N-methylglucamine, benzylamines, piperidines, and pyr rolidines and the like. Certain compounds will be acidic in nature, e. g. those compounds which possess a carboxyl or phenolic hydroxyl group. Salts of phenols can be made by heating acidic 35 compounds with any of the above mentioned bases according to procedures well known to those skilled in the art.

WO 2006/125800 PCT/EP2006/062587 54 As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. 5 The phrase "effective amount" as used herein, means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent 10 therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. 15 Administration forms The method of the invention is primarily intended for treatment in a mammal, preferably in humans and other primates, of steroid hormone dependent diseases or disorders, in particular estradiol dependent diseases or disorders, wherein the steroid hormone dependent disease or 20 disorder preferably requires the inhibition of a 17p-HSD enzyme, preferably the 17P-HSD1 enzyme. The compounds may be administered orally, dermally, parenterally, by injection, by pulmonal or nasal delivery, or sublingually, rectally or vaginally in dosage unit formulations. The term "administered by injection" includes intravenous, intraarticular, intramuscular (e.g. by depot 25 injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs), intraperitoneal, intradermal, subcutaneous, and intrathecal injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants 30 (e.g. buffers), carriers, inert solid diluents, suspensing agents, preservatives, fillers, stabilizers, anti oxidants, food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, binding agents etc., and, if desired, other active ingredients. The pharmaceutical composition may be formulated for example as immediate release, 35 sustained release, pulsatile release, two or more step release, depot or other kind of release formulations. The manufacture of the pharmaceutical compositions according to the invention may be performed according to methods known in the art and will be explained in further detail below.

WO 2006/125800 PCT/EP2006/062587 55 Commonly known and used pharmaceutically acceptable auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc. Suitable auxiliaries and further ingredients may be such 5 as recommended for pharmacy, cosmetics and related fields and which preferably are listed in the European Pharmacopoeia, FDA approved or cited in the "GRAS" list (FDA List of food additives that are 'generally recognized as safe' (GRAS)). One mode of application of the compounds of general formula (1) or of pharmaceutical 10 compositions comprising one or more of said compounds is oral application, e. g., by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the compounds suitable for the purposes of the present 15 invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatine, surface-active agents, magnesium stearate, aqueous or non aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e. g., ethereal oils), solubility enhancers (e. g., benzyl 20 benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire

TM

). In the pharmaceutical composition, the active ingredients may also be dispersed in a microparticle, e. g. a nanoparticulate, composition. For parenteral administration, the active agents can be dissolved or suspended in a 25 physiologically acceptable diluent, such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration the active agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano 30 suspensions. Transdermal application can be accomplished by suitable patches, as generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. Furthermore, also emulsions, ointments, pastes, creams or gels 35 may be used for transdermal delivery. Another suitable mode of administration is via intravaginal devices (e. g. vaginal rings) or intrauterine systems (IUS) containing reservoirs for controlled release of active agents over extended periods of time. For rectal or vaginal administration of the drug the compounds may also WO 2006/125800 PCT/EP2006/062587 56 be administered in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. 5 Another mode of application is by implantation of a depot implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber. Such implants are designed to release the active agent in a controlled manner over an extended period of time (e. g., 3 to 5 years). 10 It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the actual dosages of the agents of this invention for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the particular composition formulated, the mode of 15 administration, time of administration, route of administration and the particular site, host, and disease being treated, and furthermore the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of 20 treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests. Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound. For oral administration, an exemplary daily dose 25 generally employed will be from about 0.01 pg/kg to about 100 mg/kg of total body weight, whereby courses of treatment may be repeated at appropriate time intervals. Administration of pro-drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds. The daily dosage for parenteral administration will generally be from about 0.01 pg/kg to about 100 mg/kg of total body weight. A daily rectal dosage regimen will generally be from about 30 0.01 pg/kg to about 200 mg/kg of total body weight. A daily vaginal dosage regimen will generally be from about 0.01 pg/kg to about 100 mg/kg of total body weight. The daily topical dosage regimen will generally be from about 0.1 pg to about 100 mg administered between one to four times daily. The transdermal concentration will generally be that required to maintain a daily dose of from 0.01 pg/kg to 100 mg/kg of total body weight. 35 WO 2006/125800 PCT/EP2006/062587 57 Abbreviations and Acronyms As employed herein, the following terms have the indicated meanings. ACN acetonitrile HOnig base N-Ethyldiisopropylamine 5 Aq aqueous 35 = N(iPr)2Et = EDIPA): Bn benzyl m-CPBA m-chloroperoxybenzoic acid BOC tert-butoxycarbonyl MeOH methanol conc. concentrated mi minutes) d day(s) mom methoxy methyl 10 DAST N,N-diethylaminosulfur trifluoride40 NAD(P)[H] nicotinamide-adenine-dinucleotide DCM dichloromethane = CH 2

CI

2 (phosphate) [reduced NAD(P)] DHP 3,4-dihydro-[ 2H ]-pyran NMM N-methylmorpholine DIAD diisopropyl azodicarboxylate NMO N-methylmorpholine N-oxide DIBAH Diisobutyl aluminiumhydrid NMR nuclear magnetic resonance 15 DIPEA N,N-diisopropylethylamine 45 PG protection group DME dimethyl ethylene glycol pTosOH para-toluene sulphonic acid = 1,2-dimethoxyethane Rt Retention time DMF N,N-dimethylformamide RT room temperature DMSO dimethylsulfoxide sat saturated 20 El estron 50 STS steroid sulphatase E2 estradiol T3P propylphosphonic acid anhydride EDCI 1-(3-dimethylaminopropyl)-3- TBAF Tetrabutylammonium-fluorid ethylcarbodiimide L6sung EDCl-HCI 1-(3-dimethylaminopropyl)-3- TBDMS tert-butyl dimethyl siloxy 25 ethylcarbodiimide hydrochloride 55 TBME tert-butyl methyl ether ER estrogen receptor TEA triethylamine EtOAc ethyl acetate TEOF Triethylorthoformat (CH(OEt 3 ) h hour(s) THE tetrahydrofuran HMPA hexamethylphosphoramide THP tetrahydropyran 30 HOBT 1-Hydroxybenzotriazole Hydrate 60 TLC thin-layer chromatography HPLC High Performance Liquid Chroma- TMSCI trimethylsilylchloride / Me 3 SiCI tography TPAP tetrapropylammonium perruthen HSD hydroxysteroid dehydrogenase ate 65 WO 2006/125800 PCT/EP2006/062587 58 Numbering of compound formulas and intermediates The general structure formulas are typically designated with a number in roman format, fol lowed by a or P indicating the stereochemistry at the C15 atom of the estron core if necessary. If 5 the number of methylen groups attached at the C15 position is specified (i.e. the value of "n"), the roman number is followed by a hyphen and a number indicating the amount of methylen groups. Finally, a letter a, b or c is attached after the number "n", indicating the nature of the substituent R1 at the O-atom in C3 position of the estron core (a = hydrogen, b = methyl, and c = benzyl). The pre 14 fix C in front of the number indicates that the compound may be substituted in C2 by a residue R 10 The prefix D in front of the number that the compound may be substituted in C2 by a residue R 1 and may be additionally modified within the C16-C17 position. For example, compound IV is the general acid building block: H R1 H H nO-H (IV) 15 Therefore, a compound IVp-3a would represent a derivative of IV with P stereochemistry at C15, three methylen groups and a hydroxy group in C3 position, i.e.: O H HO OH (IVp-3a) O 0F H H = H (XXX1lla-1a)-652 H '-N HO O F This example 652 is a particular compound of the general formula XXXIII-1a, wherein R2 is a 4-fluoro-phenyl residue.

WO 2006/125800 PCT/EP2006/062587 59 General Preparative Methods The compounds of the present invention may be prepared by use of known chemical reac tions and procedures. Nevertheless, the following general preparative methods are presented to 5 aid the reader in synthesizing the 17p-HSD1 and/or STS inhibitors, with specific details provided below in the experimental section to illustrate working examples. All variable groups of these methods are as described in the generic description if they are not specifically defined below. 10 It is recognized that compounds of the invention with each claimed optional functional group may not be prepared by each of the below-listed methods. Within the scope of each method, op tional substituents may appear on reagents or intermediates which may act as protecting or other wise non-participating groups. Utilizing methods well known to those skilled in the art, these groups 15 are introduced and/or removed during the course of the synthetic schemes which provide the com pounds of the present invention. Flow Diagrams 20 The synthesis of 3, 15 substituted estrone derivatives bearing a side chain of the amide, es ter, carbonyl, hydrazone, alcohol, ether, urea, carbamate, "retro"-amide, sulfonyl urea, sulfamide, sulfamate, "retro"-sulfonamide, "retro"-carbamate, "retro"-ester or sulfonylcarbamate type in posi tion C15 is extensively described within the international application WO 2005/047303, which is hereby incorportated by reference in its entity. 25 The additional modifications of the steroidal core at positions C2, C3, C1 6 and or C1 7, which are disclosed in the present invention, may be introduced in the following order of general chemical modifications (General Synthesis Scheme). The introduction of the R substituent in C2 position if present in the final compound - has to take place first, starting from the 17p-estradiol using 30 methods well known in the art (Steps A). In parallel, the C17-OH function is oxidized to the corre sponding keto function. Depending on the desired nature of R1, a suitable group also functioning as protecting group may be introduced at this point. Then, the estron derivative of formula (V) is converted into the central intermediate, the 15, 16-unsaturated estrone of formula X (Steps B), which is further derivated in the C15 position by introduction of the basic side chain ("so called 35 building blocks"). These building blocks are reacted with the appropriate compounds carrying the R2/R4 substitutents to lead to the desired C1 5 substituted compound (Steps C). The obtained educt may be further modified within the C16 and C17 position by introducing appropriate substituents

R

10 , R 1 1 , R 1 2 and R 1 3 or by introducing a heterocyclic ring structure (Steps D). Finally, if necessary, the protection group in C1 position may be separated to deliver the C3-OH derivative or may be WO 2006/125800 PCT/EP2006/062587 60 further substituted with an alternative R 1 side chain or may be derivated to the corresponding sul phamate, phosponate, carbamate, thiophosponate, sulphonate, sulphate or phosphate compounds (Steps E). 5 GENERAL SYNTHESIS SCHEME: OH 0 H A R14 H B PG, HOO (V) 0 0 C D R14 H R14 .H PG, PG, )n I ICA O 0 XAy R 2 (X) C(I) R13 R13 R12 ER12 R14 H R14 H

R

1 0

R

1 0 PG, R A0 XA' R 2 O XA AR2 D-(1) D-(I) Step A - Introduction of a R 14 side chain in C2 position of 17p-Estradiol or Estron OH H 0 HO,0 R14 HO HO H HO 0M I HA HO 10 The introduction of various side chains in the estron core is known from the literature, e.g. Rao et al (2002) describe the synthesis of 2-methoxyestradiol, and the synthesis of 2-ethoxy estradiol was disclosed by Verdier-Pinard et al (2000). 2-Ethyl-estron may be prepared from es trone by Friedel-Crafts acetylation of estrone-3-0-methyl ether and catalytic hydrogenation, fol lowed by demethylation, which produced the desired product. Alternatively, the introduction of sub- WO 2006/125800 PCT/EP2006/062587 61 stituents on the 2-position may be obtained by using a Fries-rearrangement starting with estradiol and the reagent (RCO) 2 0 with R = lower alkyl, as described by Rao et al. (2002): After acylation, the compounds should be converted into the R-CO-substituted derivatives in C2 position. Reduc tion of the acyl function may be achieved by reduction with Pd/C and H 2 [Gonzalez et al (1982)]. 5 Alternatively, the acetoxy-group in C2-position could be oxidized with Phl(CF 3

CO

2

)

2 according to [Yoshikawa et al. (2002)]. The newly introduced hydroxy group may be further alkylated, followed by reduction of the ketone, resulting in an alkoxy-alkyl substituted estradiol derivative. An alterna tive strategy to introduce an alkoxy-alkyl group is exemplified for the methoxy-ethyl group: After MOM-protection of the 17-estradiol, the MOM-protected estradiol is iodinated [Mohanakrishnan & 10 Cushman (1999)]. Then, the MOM-group is replaced with a TBDMS group. Negishi coupling with allylbromide gives the 2-allyl substituted estrone derivative, which can be oxidised and methylated (including some protective group manipulations). Further synthetic ways to 2-alkyl-substituted es tron or estradiol derivatives have been displayed previously [see e.g. Mohanakrishnan & Cushman (1999); Day et al. (2003); Cushman et al (1995), and Lunn & Farkas (1968)] The synthesis of fur 15 ther estron derivatives with various substituents in 2-position was disclosed by Cushman et al (2002). During the introduction of the C2 side chain, the 3-hydroxy function of the steroidal core is typically protected with a methyl or benzyl group (exemplified by PG). For example, the methyl de 20 rivative can be prepared using MeJ and acetone, whereas the corresponding Benzyl-derivative may be prepared using Benzylbromid, DIPEA and acetone. Enone intermediates with other sub stituents in R 1 (= PG), in particular optionally substituted C1-C 4 -alkyl, can be prepared accordingly by using the appropriate optionally substituted C1-C 4 -alkyl-bromide or C1-C 4 -alkyl-iodide. 25 Step B - Synthesis of the 15, 16-unsaturated Estrone of formula X (Intermediate I) O R14 .H PG'1 0O The ketal of the formula (IX) can be prepared according to Nambara from the corresponding 2-substituted estron of formula V [Nambara et al. (1976)] as depicted within the following scheme 1. If not yet protected, the introduction of PG groups in C3 position can be achieved according to a 30 procedure described by Labaree (2003).

WO 2006/125800 PCT/EP2006/062587 62 SCHEME 1 000 0 0 R14 H R14 . H .R14 H Br H HH H H Br PGOPG O PG O 0 0 0 (V) O 0 0 R14 . .R14 H PG O PGO 0 0j: (IX) (X) The C17 keto function of the C2 substituted and protected estron derivative of formula (V) is protected as acetal, followed by bromination. The elimination of the bromide yielded the desired 15, 5 16-unsaturated estron. Finally, the ketal derivative is hydrolysed to give the appropriate enone derivative X. Alternatively, the enone intermediate of formula X can be prepared from the corresponding estrone derivative according to a procedure described by Poirier et al. (1991). 10 Step C - Introduction of the side chain in C15 position The "Step C" modification - the introduction of the side chain in C15 position - is carried out in two major steps: In a first step the 15, 16-unsaturated Estrone of formula X is converted into a 15 so-called building block carrying an alkyl side chain in C15 position with a terminal amino, carboxy, or alcohol function. The synthesis of some exemplary building blocks is depicted in the Experimen tal Section "Intermediates", and was fully disclosed in international patent application WO 2005/047303. 20 The second step of the "Step C" modification - the conversion of the building blocks into the desired derivatives carrying the complete side chain in C15 position - is exemplified below by using one of the following synthetic schemes as shown in Flow Diagrams I to XV. Certain formula I compounds, in which X represents a bond, A represents CO, Y represents 25 NH or NR 4 and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flow Diagram Ia.

WO 2006/125800 PCT/EP2006/062587 63 0 0 R14 . H -R14 H HO-H Hal PGO - PG 0 0 O) 0 0 (IV) 0

R

2

NH

2

/R

2

NHR

4 R14 H R2 |G H H N-HR4 PGsO 0 C-(VI) The free acid (IV) may be converted to the reactive acyl halide, in particular the acid chloride, by reaction with SOCl 2 , COCl 2 , PCI 5 or PBr 3 or the like. The amide derivatives C-(VI) may be pre pared by a base catalyzed addition-elimination reaction, where the halogen residue is substituted 5 with the appropriate amine R2NH 2 or R2NHR4 in the presence of a base, for example DIPEA. Alter natively, especially suited for derivatives with n > 2, the amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate amine. Alternatively, the amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appro priate amine as shown in Flow Diagram Ib: O O R14 H R 2 NH2/R 2

NHR

4 4 H OH PG H H H)R O PGs 10 (IV) C-(VI) Certain formula I compounds, in which X represents a bond, A represents CO, Y represents 0, and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flow Dia gram II: O O H R14 + R 2 -OH H PG ( O OG "10PG O- R2 O O 15 (IV) C-(v11) 0 The ester derivatives C-(VII) may be prepared from the free acid (IV) by esterification with the appropriate alcohol R2-OH.

WO 2006/125800 PCT/EP2006/062587 64 Certain formula I compounds, in which X represents a bond, A represents CO, Y represents a bond, and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flow Diagram III: R14 H R14. H 0-H H H H PG O G O (XXXI) (XXXIII) ------- R14 . H -R14 H H HR2 R2 PG O PGH (XXI) C-(VIII) 5 The alcohol (XXXI) may be converted to the corresponding aldehyde (XXXIII) via Dess Martin Oxidation. Subsequently the aldehyde may be converted by a nucleophilic addition elimiation reaction with a Grignard or other organometallic reagent, substituted with the appropriate R2 residue to the corresponding secondary alcohol (XXI), which thereafter can be oxidized again to the desired ketone C-(VIII). 10 Certain formula I compounds, in which X represents a bond, A represents CO, Y represents

NH-NR

4 or NH-NH, and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flow Diagram IVa. R14 . H .R14 H 0-H PG H n , PG H nHal (IV) O O O

H

2

N-NR

2

R

4

H

2

N-NHR

2 R14 .H H R2 "' N-N P 0 H H n PG H/R4 C-(XLI) 15 The free acid (IV) may be converted to the reactive acyl halide, in particular the acid chloride, by reaction with SOCl 2 , COCl 2 , PCI 5 or PBr 3 or the like. The hydrazide derivatives C-(XLI) may be prepared by a base catalysed addition-elimination reaction, where the halogen residue is substi- WO 2006/125800 PCT/EP2006/062587 65 tuted with the appropriate hydrazine H 2 N-NHR2 or H 2 N-NR2R4 in the presence of a base, for exam ple DIPEA. Alternatively, especially suited for derivatives with n > 2, the hydrazide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate hydrazine using e.g. polymer bound carbodiimid, HOBT and DCM, as shown in Flow Diagram IVb: 0 0

H

2

N-NR

2 R4 R14H H2N-NHR2 R4HH, R 0-H R H H H H N-N PG PG n H/R4 5 (IV) C-(XLI) Certain formula I compounds, in which X represents a NH, A represents CO, Y represents NH, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram Va: 0 0 0 0 H H R + R 2 -N=C=O H H ( n=-6 H H n1-6 G ONH 2 P0 N N (XV) 0 (XVI) O H R14 PG1 11 H OCA N NR 00C-(XVII) H 100 The urea derivatives of the general formula C-(XVII) may be prepared by the reaction of the amine building block (XV) with an appropriately substituted Isocyanate (R2-N=C=O). After the addi tion, the ketal function is converted into the keto function. Alternatively, the amine may be first re acted with carbodiimidazol or triphosghen to form a reactive carbamoyl compound, which than can 15 react further with a suitable amine R2R4-NH. A further synthesis variant may use the unprotected amine (XXIX) as starting material for the reaction with an appropriately substituted Isocyanate (R 2 N=C=O) as shown in Flow Diagram Vb 0 0 H H + R 2 -N=C=O H H ( n=1-6 H H ( n=1-6 R11_ 0C H 0 NH*HCI R1O R/NfR2 (XXIX) R3 C-(XVII) 0 WO 2006/125800 PCT/EP2006/062587 66 Certain formula I compounds, in which X represents a -NH-, A represents SO 2 , Y repre sents NH, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram VI 0 0 o 0 R14 HR14 H PGH H ( n=1-6 +Br-R 2 H H o NH PG (XV) O s (XVI) R2-N 0 R14 .HPG H H ( ) PGs O HN| R2 C-(XIX) S-N 0 5 In a first step, the amine building block (XV) may be converted into a protected, for example Boc-protected, sulfamide compound by a reaction with the appropriately protected chlorosulfonyl isocyanate. In a second step, the protected sulfamide compound is allowed to react with the ap propriate Bromo-reagent (R2-Br) to provide the still protected, substituted sulfamide derivative of the formula (XVIII). After deprotection, the desired N-substituted sulfamide derivative of formula C 10 (XIX) is obtained. Certain formula I compounds, in which X represents a NH, A represents CO, Y represents 0, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram VII: o 0 0 O + CI1* H R14 H O-R2 R14 PG H H ( )1PG6 0 NH 2 HN 0-R2 15 (XV) C-(XX) 150 The carbamate derivatives of the general formula C-(XX) may be prepared by the reaction of the amine building block (XV) with an appropriate chloroformic acid ester (R 2 -0-CO-CI). After the addition-elimination reaction, in a second step the ketal function is converted into the keto function. 20 Certain formula I compounds, in which X represents a NH, A represents SO 2 , Y represents 0, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Dia gram VIII: WO 2006/125800 PCT/EP2006/062587 67 O0 0 00 11 O + CI-S-0-R2 H H R14 . . H PG H H )n=16 O NH 2 HN/ S (XV) C-(XXII) // O-R2 0 The sulfamate derivatives of the general formula C-(XXII) may be prepared by the reaction of the amine building block (XV) with an appropriate chlorosulfonic acid ester (R 2 -0-S0 2 -CI). After the addition-elimination reaction, in a second step the ketal function is converted into the keto function. 5 Certain formula I compounds, in which X represents a NH, A represents CO, Y represents a bond, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram IXa: O0 0 /0 H H + R2 O R14 R1- : Hal H H ( ) H H ( PG, PGsO NH 0 R2 (XV) C-(XX111) H 10 The "retro"-amide derivatives of the general formula C-(XX111) may be prepared by the reac tion of the amine building block (XV) with an appropriate acid halide, e.g. an acid chloride (R2-CO Cl). After the addition-elimination reaction, in a second step the ketal function is converted into the keto function. Alternatively, the reaction with an appropriate acid halide, e.g. an acid chloride (R 2 CO-Cl), can be performed using the amino-hydrochloride salt of the estrone (XXIX) as starting ma 15 terial as shown in the following Flow Diagram IXb: 0 0 0 H R14 H + R2 O R14 H a l N N ( H H ( n=16 PG0 H H ( )n=16 PGsO NHP*HCI 0 HN R2 0 (XXIX) C-(XXIII) Certain formula I compounds, in which X represents a NH, A represents SO 2 , Y represents a bond, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow 20 Diagram Xa: WO 2006/125800 PCT/EP2006/062587 68 0 0 0 R14 H + R2-SO2-Hal R14 H H H PG( 0 2H0 O N2 OHN_ // (XV) s-xv (XV)C-(XXIV) // 'R2 The sulfonamide derivatives of the general formula C-(XXIV) may be prepared by the reac tion of the amine building block (XV) with an appropriate sulfonic acid halide, e.g. a sulfonic acid chloride (R2-SO 2 -CI). After the addition-elimination reaction, in a second step the ketal function is 5 converted into the keto function. Alternatively, the reaction with an appropriate sulfonic acid halide, e.g. sulfonic acid chloride (R2-S0 2 -CI), can be performed using the amino-hydrochloride salt of the estrone (XXIX) as starting material as shown in the following Flow Diagram Xb: 0 0 R14 H + R2-SO-Hal R14 H H H n=1-6 H H ( )n=1-6 0 0 O NH2*HCI 0 HNs / C-(XXIV) // R2 10 Certain formula I compounds, in which X represents a NH, A represents CO, Y represents

NH-SO

2 , and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram XI: 0 0 0 R14 H + R 2 -S0 2 -N=C=O R14 PG H H NH1. PGn O NH2 H R Y PR2 (XV) C-(XXV) 0 0 The sulfonyl urea derivatives of the general formula C-(XXV) may be prepared by the reac 15 tion of the amine building block (XV) with an appropriately substituted sulfonyl isocyanate (R2-SO 2 N=C=O). After the addition, the ketal function is converted into the keto function. Certain formula I compounds, in which X represents an 0, A represents CO, Y represents

NR

4 , and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow 20 Diagram XII: WO 2006/125800 PCT/EP2006/062587 69 0 0 R14 H + R 2 -N=C=O R14 H | H H ( n=1-6 H H ( )n=16 PGsO PGOH OH H (XXXI) C-(XXVI) Y R2 0 The "retro"-carbamate derivatives of the general formula C-(XXVI) may be prepared by the reaction of the estrone alcohol building block (XXXI) with an appropriately substituted isocyanate

(R

2 -N=C=O) and subsequent purification. 5 Certain formula I compounds, in which X represents a 0, A represents CO, Y represents a bond, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram XIII: 0 0 R14 H + R 2 -COOH R14 H H H ( n16H H )=1 PGO OH PG( 0 0O R2 (XXXI) C-(XXVII) 0 10 The "retro"-ester derivatives of the general formula C-(XXVII) may be prepared by the esteri fication of the estrone alcohol building block (XXXI) with the appropriate carboxylic acid R2-COOH and subsequent purification. Certain formula I compounds, in which X represents a 0, A represents CO, Y represents 15 NH-S0 2

-NR

4 , and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram XIV: O 0 H Cl-S0 2 -N=C=O H R14 . ., R14. . H H ( n=16 H H ( )n=16 0 PGI OH PG H0IH 0 OO O N-S-CI (XXXI) Of 11 0 H

R

2

R

4 -NH R14 _______ ____HH ()f= 0 PG O H ,R2 O N-S-N C-(XXVIII) R4 0 WO 2006/125800 PCT/EP2006/062587 70 The sulfonylcarbamate derivatives of the general formula C-(XXVIII) may be prepared by a two-step synthesis: In a first step, the estrone alcohol building block (XXXI) is converted to the chlorosulfonylcarbamate intermediate by reaction with chlorosulfonyl isocyanate. Subsequently, the intermediate is allowed to react with the appropriate primary or secondary amine HNR2R4 in in or 5 der to give the desired sulfonylcarbamate derivative. Certain formula I compounds, in which X-A-Y represents 0, and R2 is different from H may be prepared by a reaction as shown in Flow Diagram XV: 0 0 H BrMg-(CH 2 )n-O-R 2 H | H N N ( PG PGl n-R 0 O O-R2 (X) C-(XXX) 10 The ether derivatives of the general formula C-(XXX) may be prepared the reaction of an appropriate Grignard reagent BrMg-(CH 2 )n-O-R 2 (for n = 3-6) with the 15,16-unsaturated estrone derivative of formula X. Alternatively, ether derivatives may be prepared by derivatisation of the corresponding alcohol of the general formula (XXXI). 15 The synthesis of certain formula I compounds, in which X-A-Y represents 0, R2 represents H, and n represents an integer from 1 to 6, according to general formula C-(XXXI) is decribed within the section "Intermediates". O H C-(XXXI) PG O OH 20 Step D - Modification of the C17-keto function or introduction of a heterocyclic ring system in C16-C17 Since the C15-side chain as well as the C2 side chain were already introduced, it is clear for 25 the skilled artisan, that, where necessary, functional groups in the alcohol D(I)-OH may be pro tected in known manner and the protecting group or groups removed at the end of the reaction.

WO 2006/125800 PCT/EP2006/062587 71 Step D - 1, for compounds when the substituents R 1 0, R", R 1 2 and R 1 3 together with the carbon atoms, to which they are attached, form a structure -CR' 3 R 1-CR"Rl 0 -, which is selected from the group of (a)

C

2 5 ,forming a compound of general formula D-(1)-(=CF 2 )

CF

2 H H PG, I n X A R2

D-(I)-(=CF

2 ) (b) F F ,forming a compound of general formula D-(1)-F 2 F F R14 .H H H PG,.. )n 0 A' YR2 D-(I)-F2 10 (c)

CHF

2 F CF 3 and ,forming a compound of general formula D-(1)-(c) R12 R14 H H H PG, -C* n X A R2 D-(I)-(c) wherein R 1 2 represents -F, -CF 3 , or -CF 2 H; and 15 WO 2006/125800 PCT/EP2006/062587 72 (d)

CHF

2 F CF 3 and ,forming a compound of general formula D-(1)-(d) R12 R14 H H PG cn 0 X A R 2 D-(I)-(d) , or wherein R represents -F, -CF 3 , or -CF 2 H. 5 For synthesis of some D-(I) compounds and in order to enable library synthesis, it might be necessary that some of the reaction steps explained under "STEPS C - the introduction of the C1 5 side chain" have to be carried out after having introduced the respective fluoro group. A typical scenario might be that after optional introduction of the R14 residue in C2 position, the 15,16 10 unsaturated intermediate (X) is prepared. This is further derivatized to the appropriate acid, alcohol, amid or alkenyl intermediate ("building block" - see section "Intermediates"). Then, the fluoro group is introduced into C17 position of the steroidal core using a synthesis scheme as described in more detail below. The so-obtained intermediate is then used for optional further modification of the C15 side chain and introduction of the R2/R4 substituents. Finally any protection groups in C3 position 15 might be cleaved off. D-(1)-(a): Synthesis of compounds, wherein R 1 0 and R 1 1 both represent -H and R 1 2 and R 13 to gether represent =CFa F F 0 / R14 H R14 .H H H H N H Ho PGs ( )n PG 0n O-(X)A' R 2 O0s'R C-(1)

D-(I)-(=CF

2 ) 20 The introduction of a =CF 2 group in C17 position of the estron core is a reaction well known in the art, see e.g. Edwards et al (1990) using F 2 CP(O(Ph) 2 as fluorinating reagent, or by using the Horner reaction with F 2 CP(O)(OEt) 2 as fluorinating reagent Schwarz et al (2001). In addition, the reaction can be carried out according to procedures described within international patent applica tion WO 96/28462. Subsequent deprotection of the C3-hydroxy function may be obtained using 25 standard techniques.

WO 2006/125800 PCT/EP2006/062587 73 D-(1)-(b): Synthesis of compounds, wherein R 1 0 and R" both represent -H and R" and R" both individually represent -F F F R14 .H H H PG, . )n X A YR2 D-(I)-F2 Reaction Scheme: 0 F F R4 . H R14 .H H H H PGs PGn O XsA YR2 OA YR2 C-(I) 5 D-(I)-F2 The difluorination of the C17 atom of the estron core is a reaction well known in the art and was already disclosed in US patents US 3,413,321 and US 3,347,878. Furthermore, the difluorina tion of the C17 atom of the estron core may be achieved using the DAST (N,N-diethylaminosulfur trifluoride) reagent [Liu et al (1992)]. 10 D-(1)-(c): Synthesis of compounds, wherein R 1 0 , R" and R 13 all represent -H and R 12 is selected from -F, -CF-, and -CF2H R12 R14 .H HH PG, on O X A 'R2 D-(I)-(c) 1. R1 represents -F O F R14 H R14 H H H()H H PG (n PG, / n 0 x 0 x '*' 15 OC-(I) XA 'YR2 OD-(I)-(c)-F XA 'YR2 The mono-fluorination of the C17 atom of the estron core is a reaction well known in the art and may be performed according to the disclosure of US patent US 3,275,623.

WO 2006/125800 PCT/EP2006/062587 74 2. R1 represents -CF2H o F P R14 C H H HR14 F SA R2 PG X C-(1) CF 2 H D-(I)-(a)=CF 2 A R 2 R14 H PG 1i H D-(I)-(c)-CF 2 H X A R 2 The desired compound of the general formula D-(1)-(c)-CF 2 H may be obtained by hydrogena tion of the corresponding 17-difluoromethylene substituted derivative, the synthesis of which is de 5 scribed above. If desired, the protection group is subsequently removed. 3. R1 represents -CF 0

CF

3 OH R14 H R14.H H Ho1 N E PGs /' H H 0 X' PG, )n C-(1) A R2

CF

3

CF

3 HH R4H R14 H PG'O X H H OXA PG..)n XA R2 0X Y A NR2 D-(I)-(d)-CF 3 D-(I)-(c)-CF 3 The introduction of the -CF 3 group in C17 position of the estron core may be performed ac 10 cording to Wang & Ruan (1994). Then, the double bond in C16, C17 position is introduced by acidic elimination to deliver a compound of general formula D-(1)-(d)-CF 3 . The unsaturated deriva tive may be converted into the corresponding saturated compound by hydrogenation. If desired, the protection group is subsequently removed to deliberate the 3-hydroxy function. 15 D-(1)-(d): Synthesis of compounds, wherein R 1 0 represents -H, R" together with R 1 3 forms a bond, and R is selected from -F, -CF3, and -CF9H R12 H D-(I)-(d) PGs / )n 0A XsA'R 2 WO 2006/125800 PCT/EP2006/062587 75 1. R1 represents -F F F F R14 H R14 H |G~ H Ho PGH H PGs )n PGs /) n D-(1)-F2 A . R2 0 D-(I)-(d)-F NA' R2 The 17-monofluorinated, 16,17-unsaturated estron derivative may be obtained starting from the corresponding 17-difluorinated compound, the synthesis of which was explained above, ac 5 cording to the procedure described by Liu et al. (1992). If desired, the protection group can be sub sequently removed. 2. R1 represents -CF2H o F F R14 HH R14 PG, H H OG X, .Y "'2PG n A NR2 OX Y~ C-(I) D-(I)-(a)=CF2 ',A'Y R2

CF

2 H R14 H D-(I)-(d)-CF 2 H PG, 0 X A R 2 10 The desired compound of the general formula D-(1)-(d)-CF 2 H may be obtained by Pd catalyzed isomerization of the double bond of the corresponding 17-difluoromethylene substituted derivative, the synthesis of which has been described above. If desired, the protection group can be subsequently removed. 15 3. R1 represents -CF H CF 3 OH R14 H :. R14 H PG O PG H )n A R 2 0 X Y C-(1) CF 3 A R2 R14 H R 1 H D -(I)-(d )-C F 3 PG, (| )n OX, A R2 WO 2006/125800 PCT/EP2006/062587 76 The introduction of the -CF 3 group in C17 position of the estron core may be performed ac cording to Wang & Ruan (1994). Then, the double bond in C16, C17 position is introduced by acidic elimination to deliver the 16, 17 unsaturated estron derivative of general formula D-(1)-(d)

CF

3 . If desired, the protection group is subsequently removed to deliberate the 3-hydroxy function. 5 Step D - 2, for compounds when the substituents R 1 0, R", R 1 2 and R 1 3 together with the carbon atoms, to which R 1 0 , R", R 1 2 and R 1 3 are attached, form a heterocyclic 5- or 6-membered ring, which is partly unsaturated or aromatic, which contains one, two or three heteroatoms inde 10 pendently selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, wherein one heteroatom is directly attached to the C17 C-atom of the steroidal core; and which ring is optionally substituted with an alkyl group. The synthesis of estron derivatives carrying an additional heterocyclic ring in C16-C17 posi 15 tion of the steroidal core has already been disclosed within international patent application WO 2004/085457; the synthesis schemes depicted there can also be applied to the intermediates of the present invention in order to receive the compounds of the present invention. Some reac tions are exemplified in more detail below. 20 Preferably, the substituents R 1 0 , R", R 12 and R 1 3 together with the carbon atoms, to which

R

10 , R", R 1 2 and R 1 3 are attached, form a heterocyclic 5- or 6-membered ring to provide a com pound of one of the following formulas R15 N N_ N R14 H R14 H H H H A R1 )n R1 ) OX, A YR2 O, XA'Y "R2 O' N O R14 H R14 H H | H R!, ( )n R, 0 )n 0 XA YR2 O XA' R 2 , or N R14 H W, H H ) 25 X A R2 wherein R 1 5 represents -H or -(C-C 4 )alkyl.

WO 2006/125800 PCT/EP2006/062587 77 For synthesis of D-(II) compounds it might be necessary that some of the reaction steps ex plained under "STEPS C - the introduction of the C1 5 side chain" have to be carried out after hav ing introduced the heterocyclic ring system. A typical scenario might be, that after optional introduc tion of the R residue in C2 position, the 15,16-unsaturated intermediate (X) is prepared. This is 5 further derivatized to the appropriate acid, alcohol, amid or alkenyl intermediate ("building block"). Then, the heterocyclic ring system is introduced including the C16-C17 carbon atoms attached to the D-ring using a synthesis scheme according to WO 2004/085457 or as described below. The so obtained intermediate is then used for further modification of the C15 side chain and introduction of the R2/R4 substituents. Finally any protection groups in C3 position might be cleaved off. 10 D-(II)-(a) and D-(II)-(b): Synthesis of compounds of formula D-(II)-(a) and D-(II)-(b)

R

15 N_. 15 NN N_ N R14 H R 1 4 H PGsH PG, n Xy A R 2 and XA YR 2 The pyrazole-unit is known in steroid-chemistry and is constructed in 3 steps as depicted in the following scheme for D-(II)-(a): 0 O OH R14 H .

R14 H --- GHH H R* PGHH R PG'O R PG, O R15 O \ N R14 H --- , R14 . H N N R* H H R* PGs PGs _; 15 0 0 The R* residue may represent the completely introduced C15 side chain -(CH 2 )n-X-A-Y-R 2 , or may represent an intermediate side chain such as -CH 2

-CH=CH

2 , or -CH 2

-CH

2

-CH

2

-CH=CH

2 (see also SCHEMES 7B and 7C for introduction and further modification of this alkenyl side chain). 20 First a a-hydroxymethylene moiety is introduced with NaOMe (or NaH) and ethylformate [W6lfling et al (2003), Oda et al (1989), Schneider et al (1983)]. After methylation with K 2 C0 3 and Mel (WO 2004/85457) or MeOH and CeCl 3 [Akanni & Marples (1993)], the ring is closed with the appropriate hydrazine or alkylhydrazine, e.g. methylhydrazine [Xenos & Catsoulacos (1985)]. Al ternatively, the methylpyrazine is constructed from the methoxymethylene compound with hydra 25 zine, followed by alkylation with Mel.

WO 2006/125800 PCT/EP2006/062587 78 D-(II)-(c) and D-(II)-(d): Synthesis of compounds of formula D-(II)-(c) and D-(II)-(c) O' N O R14 .H .R14 .H R H H n H 0, XA Y"R2 0 X, A Il R2 and A R The introduction of the isooxazole group as attached heterocycle to the D-ring of the ster oidal core may be achieved according to the synthesis of the corresponding pyrazole derivative 5 and is constructed in 3 steps as depicted in the following scheme for D-(II)-(c/d): 0 O HOH R14 HNH0 C R14 H - H H R*H PGs G PG0 H H R* H 0 R* The R* residue may represent the completely introduced C15 side chain -(CH 2 )n-X-A-Y-R 2 , or may represent an intermediate side chain such as -CH 2

-CH=CH

2 , or -CH 2

-CH

2

-CH

2

-CH=CH

2 (see also SCHEMES 7B and 7C for introduction and further modification of this alkenyl side chain). 10 First a a-hydroxymethylene moiety is introduced with NaOMe (or NaH) and ethylformate [W6lfling et al (2003), Oda et al (1989), Schneider et al (1983)]. After methylation with K 2 C0 3 and Mel (WO 2004/85457 A2) or MeOH and CeCl 3 [Akanni & Marples (1993)], the ring is closed with the appropriate hydroxylamine. 15 D-(II)-(e): Synthesis of compounds of formula D-(II)-(e)

N-

R14 .H H H RW, )n O, yA Y R2 The synthesis of the C15 estrone derivatives with an attached pyridin ring to the D-ring of the steroidal core is fully disclosed in internation patent application WO 2004/085457. 20 WO 2006/125800 PCT/EP2006/062587 79 Step E - Modification of the R1 residue In case that R1 represents -H, or optionally substituted -(C1-C6)alkyl, phenyl or -(CI C6)alkylphenyl, then the substituent may already have been introduced during synthesis of the In 5 termediates as explained for R1 = H, R1 = methyl and R1 = benzyl. In case of further modification of the 3-OH function to a sulphamate, carbamate, phosphonate, thiophosphonate, sulphonate, phosphate or sulphate group, this may be obtained by one of the following reactions: SULPHAMATE COMPOUND PREPARATION 10 The sulphamate compounds of the present invention may be prepared by reacting the corre spondingly substituted estron derivative of the general formula D-(I) with a free 3-OH group with a suitable sulfamoyl chloride of the general formula R 3

R

3

'NSO

2 CI. R13 R13

R

1 2

R

1 2 R14 H R 10 CI-S0 2

-NR

3

R

3 ' R14 H R11 A 1O H H ( InR3, Il n HO X'',R2 RN-S-a XA R2 ~AN2 R3 11A NR2 D-(1)-OH (I)-S0 2

-NR

3

R

3 ' 15 Typical conditions for carrying out the reaction are as follows: Sodium hydride and a sulfa moyl chloride are added to a stirred solution of the alcohol D(I)-OH in anhydrous dimethyl forma mide at 0*C. Subsequently, the reaction is allowed to warm to RT whereupon stirring is continued for a further 24 h. The reaction mixture is poured onto a cold saturated solution of sodium bicar 20 bonate and the resulting aqueous phase is extracted with DCMe. The combined organic extracts are dried over anhydrous MgSO 4 . Filtration followed by solvent evaporation in vacuo and co evaporated with toluene affords a crude residue which is further purified by flash chromatography. Alternatively, sulfamoyl chloride (1 mmol) was added to a stirred solution of the alcohol D(I) 25 OH (0.5 mmol) in anhydrous N,N-dimethylacetamide (0.75 ml) at 0*C. The mixture was stirred at RT for 3 h and then poured into cold brine (10 ml). The resulting mixture was extracted with EtOAc (3x10 ml), the combined organic layers were washed with brine (10 ml), dried (MgSO 4 ), and con centrated under reduced pressure. The product was purified by flash chromatography on silica gel. 30 Where necessary, functional groups in the alcohol D(I)-OH may be protected in known man ner and the protecting group or groups removed at the end of the reaction. Preferably, the sulphate compounds are prepared according to the teachings of Page et a/ (1990).

WO 2006/125800 PCT/EP2006/062587 80 CARBAMATE COMPOUND PREPARATION The carbamate compounds of the present invention may be prepared by derivatisation of the correspondingly substituted estron derivative of the general formula D-(1) with a free 3-OH group.

R

1 3

R

1 3

R

1 2

R

1 2 R 1 4 . H -R i o R 1 4 H :R 1 0 H H 0H R 1 0 HHP R31 HI- H H HO x A R2 R3 N X A" R2 D-(I)-OH

(I)-CO-NR

3

R

3 ' 5 Typical conditions for carrying out the reaction are as follows: 1 eq Estrone derivative D-(1) OH, 3 eq N-methyl-morpholine and 1/3 eq Triphosgen were dissolved in DCM and stirred for 30 min at 0*C. Then, 1 eq of the desired amine was added and the reaction mixture stirred for 12 h at RT. Thereafter the reaction mixture was quenched by adding 1 M NaHCO 3 . The organic layer was separated and extracted with 1 M KHSO 4 and 1 M NaCl. After drying over Na 2

SO

4 the solution was 10 evaporated to dryness and purified by column chromatography. Where necessary, functional groups in the alcohol D(I)-OH may be protected in known manner and the protecting group or groups removed at the end of the reaction. SULPHONATE COMPOUND PREPARATION 15 The sulphonate compounds of the present invention may be prepared starting from the cor respondingly substituted estron derivative and by suitably combining the teachings of Page et a/ (1990) and published international patent application WO 93/05063.

R

13

R

13 R12 R12 R11 R11 R H H | A ( On | H H ( )n HO Xy A R2 R3-S-O y YR2 D-(I)-OH 0 (I)-S 2

-R

3 20 PHOSPHONATE COMPOUND PREPARATION The phosphonate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative and by suitably combining the teachings of Page et a/ (1990) and published international patent application WO 93/05063. R13 R13

R

1 2

R

1 2 R14 H R14 H

R

1 0 R10 H H OR16 H C n n HO X' R3-P-O XA R2 DA)OR2 ( RA 1)R2 D-(l)-OH 0 (I)-PO(OR 16

)-R

3 WO 2006/125800 PCT/EP2006/062587 81 THIOPHOSPHONATE COMPOUND PREPARATION The thiophosphonate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative and by suitably combining the teachings of Page et a/ 5 (1990) and published international patent application WO 93/05063. R13 R13

R

1 2

R

1 2 R14 H R14 H

R

1 0 R10 H H OR16| H HO X' R3-P-O XA R 1 A NR2 11 A .1"R2 D-(I)-OH (I)-PS(OR 1 6

)-R

3 SULPHATE COMPOUND PREPARATION The sulphate compounds of the present invention may be prepared starting from the corre 10 spondingly substituted estron derivative using known sulfating reagents, such as complexes of sulfur trioxide with Lewis bases such as trialkylamines (e.g. S0 3 *Et 3 N), DMF, or pyridine. R13 R13 R12 R12 H R' R14 H R14R 10 i

R

10 A H H HO YR3-0-i0 X, Y Xs'R 1Y1I A R D-(1)-OH A R 2 0 (l)-S0 2 -0-R 3 PHOSPHATE COMPOUND PREPARATION 15 The phosphate compounds of the present invention may be prepared starting from the cor respondingly substituted estron derivative by phosphorylation using e.g. phosphoramidite chem istry or treatment with pyrophosphoric tetrachloride. R13 R13

R

1 2

R

1 2 R14 H R14 H

R

1 0 R10 A (H OR16| H HO X Y R3-0-P-O X Y AR2 .A NR2 D-(1)-OH (I)-PO(OR 1 6

)-O-R

3 20 WO 2006/125800 PCT/EP2006/062587 82 Experimental Examples of preparations of compounds of the invention are provided in the following de tailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound 5 is referenced back to these exemplary preparative steps. In single compound synthesis as well as in combinatorial synthesis all reactions were stirred magnetically or shaked with an orbital shaker unless otherwise indicated. Sensitive liquids and so lutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber 10 septa, in these cases the reaction were carried out under a positive pressure of dry argon or dry nitrogen. Commercial grade reagents and solvents were used without further purification. Unless otherwise stated, the term "concentration under reduced pressure" refers to use of a Buchi or Heidolph rotary evaporator ("Rotavapor") or vaccum centrifuges ("GeneVac" or "Christ al 15 pha RVC") at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (*C). Unless otherwise indicated, all parts and percentages are by volume. Thin-layer chromatography (TLC) was performed on Merck@ pre-coated glass-backed silica gel or aluminium sheets 60A F-254 250 pm plates. Visualization of plates was effected by one or 20 more of the following techniques: (a) ultraviolet illumination (254 nm or 266 nm), (b) exposure to iodine vapor, (c) spraying of the plate with Schlittler's reagent solution followed by heating, (d) spraying of the plate with anisaldehyde solution followed by heating, and/or (e) spraying of the plate with Rauxz reagent solution followed by heating. Column chromatography (flash chromatog raphy) was performed using 230-630 mesh ICN, SiliTech 60A silica gel. 25 Melting points (mp) were determined using a Reichert Thermovar melting point apparatus or a Mettler DSC822 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Perkin Elmer spectrophotometer. 30 Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker ARX (400 MHz) or Bruker ADVANCE (500 MHz) spectrometer with either Me 4 Si (5 0.00) or residual pro tonated solvent (CHCl 3 5 7.26; CHD 2 0D 5 3.30; DMSO-d 5 5 2.50) as standard. Carbon ( 1 3 C) NMR spectra were measured with a Bruker ARX (100 MHz) or Bruker ADVANCE (126 MHz) spectrome 35 ter with either Me 4 Si (5 0.00) or solvent (CDCl 3 6 77.05; CD 3 0D 5 49.0; DMSO-d 6 5 39.45) as stan dard. HPLC electrospray mass spectra (HPLC ES-MS) were obtained using the following method and equipment: Samples were separated by reversed phase high pressure liquid chromatography WO 2006/125800 PCT/EP2006/062587 83 (RP-HPLC) coupled to a quadrupol MS. HPLC was performed at a flow of 1000 pl/min using Xter raMS C18 columns (i.d. 4.6 mm, length 50 mm, particle size 2.5 pm) or Phenomenex Luna C18(2) 30*4.6mm columns. For most samples, a gradient from 0% eluent B to 95% B was run in 10 min, with eluent A consisting of water, 10 mM ammonium-acetate at pH 5 + 5% acetonitrile and eluent B 5 consisting of acetonitrile. Two different setups were used: 1. Waters Alliance 2795 coupled to a Waters ZQ MS, a Waters 2996 diode array detector (DAD) and an evaporative light scattering de tector (ELSD, EL-ELS1000, PolymerLabs). Ionization: electrospray positive and negative mode ES +/-; or 2. LC200 pump (PE) coupled to an API100 MS (Applied Biosystems Sciex), a variable wave length detector Waters 2487 set to 225 nm, and an ELSD (Sedex 75), ES+. In both setup versions 10 spectra were scanned with a scan range of m/z 100 to 800 or 100 to 900. Gas chromatography - mass spectra (GC-MS) analyses were performed with an Agilent 6890 gas chromatograph equipped with an DB-5MS column (0.25 i.d., length 30 m) and an Agilent 5973 MSD quadrupol detector (ionization with electron impact (EI) at 70eV; source temperature 15 230*C). Elemental analyses were conducted by a VarioEL elemental analyzer (Elementar Analysen systeme) for determination of C, H, and N. Acetanilide was used for conditioning and calibration. 20 NMR spectra, LRMS, elemental analyses and HRMS of the compounds were consistent with the assigned structures.

WO 2006/125800 PCT/EP2006/062587 84 Intermediates 1. Estron derivatives substituted in C2 position of the steroidal core of formula (V) (Step A) 5 3-Benzyloxy-estra-1,3,5(10)-trien-2,17p-diol (V-C2-A) 3-Benzyloxy-estra-1,3,5(10)-trien-2,17-diol was prepared starting from estradiol by introduc tion of the hydroxy side chain in C2 position as described by Rao et al. (2002) in which a Fries rear rangement and a Baeyer Villiger reaction is used. 10 Detailed Synthesis Estra-1,3,5(10)-triene-3,17p-diol diacetate (C2-2): Under an N 2 -atmosphere, Ac 2 O (375 ml, 3.993 mol) was added dropwise during 20 min to a solution of estradiol (150 g, 0.551 mol) in pyridine (1500 ml). The clear colourless solution obtained was stirred at RT overnight. The reaction mixture was then cooled to 0*C and MeOH (375 ml) was 15 added dropwise during 25 min. The reaction mixture was stirred at 0*C for 2 h, then allowed to warm to RT and concentrated in vacuo. The residue was recrystallized from hot MeOH to yield (C2-2) (176 g, 90%) as white crystals. 2-Acetyl-estra-1,3,5(10)-triene-3,17p-diol 17-acetate (C2-3): 20 Under an N 2 -atmosphere, ZrCl 4 (530 g, 2.27 mol) was added in one portion to a solution of (C2-2) (176 g, 0.493 mol) in DCM (13 I). The turbid yellow mixture obtained was stirred at RT for 48h. The reaction mixture was cooled to 0*C, ice water (3 I) was added and the mixture was al lowed to warm to RT overnight. The mixture was washed with H 2 0, sat NaHCO 3 (aq), brine, dried over Na 2

SO

4 , filtered, and concentrated in vacuo to yield (C2-3) (167 g, 95%) as a yellow powder. 25 2-Acetyl-3-benzyloxy-estra-1,3,5(10)-triene-17p-ol 17-acetate (C2-4): Under an N 2 -atmosphere, K 2 C0 3 (97 g, 0.702 mol) was added in one portion to a solution of (C2-3) (167 g, 0.468 mol), benzyl bromide (61.6 ml, 0.515 mol) and 18-crown-6 (4.7 g, 0.018 mol) in acetone (1 1). After 108 h at Ttwem=5 6 *C, the reaction mixture was allowed to cool to RT, poured 30 into H 2 0, stirred for 1 h after which the turbid mixture was filtered over a glass fritted filter. The resi due was washed with H 2 0, and dried in vacuo to yield (C2-4) (209 g, 100%) as a brown solid. 3-Benzyloxy-estra-1,3,5(10)-triene-2,17p-diol diacetate (C2-5): Under N 2 atmosphere, NaH 2

PO

4 (2.496 mol) was added to a solution of C2-4 (167 g, 0.468 35 mol) in DCM (7 I). Then m-CPBA (75% with H 2 0, 0.889 mol) was added portionwise during 10 min. The turbid mixture obtained was stirred at RT for overnight. The reaction mixture was poured into

H

2 0, and the mixture obtained was stirred for 1 h. The organic layer was isolated and the aqueous layer was extracted with DCM. The combined organic layers were washed with H 2 0, 10% Na 2

SO

3 WO 2006/125800 PCT/EP2006/062587 85 (aq), half-sat. NaHCO 3 (aq), brine, dried over Na 2

SO

4 , filtered, and concentrated in vacuo to yield C2-5 (247 g, quant.) as a clear yellow powder. 3-Benzvloxy-estra-1,3,5(10)-triene-2,17p-diol (V-C2-A): 5 A solution of KOH (4.46 mol) in H 2 0 (5 I) was added to a solution of (C2-5) (511 g, 1.181 mol) in THF (5 I) and MeOH (5 I). The mixture obtained was stirred at Ttwem=65 *C overnight, and then allowed to cool to RT. The reaction mixture was acidified with conc. HOAc to pH 4 and diluted with H 2 0and EtOAc (1:3). The organic layer was isolated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 , filtered, and con 10 centrated in vacuo to yield 358 g brown solid. The solid was triturated with TBME (2 L) for 2 h, fil tered over a glass fritted filter (P2) and the residue was washed with TBME, then with acetone, and dried in vacuo to yield (C2-A) (256 g) as an off-white solid. The combined filtrates were concen trated in vacuo to yield 125 g brown resin. The resin was dissolved in DCM, applied to Si0 2 and eluted with DCM:NH 3 7N in MeOH = 97.5: 2.5 to yield 76 g yellow solid (Rf= 0.39). The solid was 15 triturated with TBME (250 ml), filtered over a glass fritted filter (P4). The residue was washed with DCM and dried in vacuo to yield (V-C2-A) (15.4 g) as an off- white solid. Total yield: 61%. 3-Benzyloxy-2-methoxy-estra-1,3,5(10)-triene-17one (V-C2-B): 3-Benzyloxy-2-methoxy-estra-1,3,5(10)-trene-17 onelvas prepared starting from (V-C2-A) 20 according to the procedure described by Rao et al. (2002) and within US 6,043,236. Detailed Synthesis 3-Benzyloxy-2-methoxy-estra-1,3,5(10)-trene-17p-ol (C2-6): Under an N 2 -atmosphere, LiOH-H 2 O (16.2 g, 0.386 mol) was added to a solution of (V-C2-A) 25 (118 g, 0.312 mol mol) in THF (1.5 I). After adding Me 2

SO

4 (0.350 mol) the mixture obtained was stirred at 55*C for 3h. The mixture was allowed to cool to RT overnight, concentrated in vacuo, and the residue was dissolved in DCM. The organic layer was washed with H 2 0, brine, dried over Na 2

SO

4 , filtered, and concentrated in vacuo to yield (C2-6) (115 g, 94%) as orange resin. 30 3-Benzyloxy-2-methoxy-estra-1,3,5(10)-trene-17one (V-C2-B): To a mixture of (C2-6) (118 g, 0.301 mol) and TPAP (0.014 mol) in acetone (2 I), NMO (0.448 mol) was added portion-wise. The mixture obtained was stirred at RT overnight, and option ally filtered over Celite. The filtrate / reaction mixture was concentrated in vacuo to yield 128 g black solid. The solid was purified by column chromatography (Si0 2 with DCM) to yield (V-C2-B) 35 (97 g, 83%) as a pale yellow solid (Rf = 0.78). 3-Benzyloxy-2-ethyl-estra-1,3,5(10)-triene-17one (V-C2-C): 3-Benzyloxy-2-ethyl-estra-1,3,5(10)-triene-17one was prepared starting from (C2-4) by per forming a Wolff-Kishner reduction to obtain the ethyl side chain. The oxidation of the C17 hydroxyl WO 2006/125800 PCT/EP2006/062587 86 function was achieved by TPAP oxidation using the procedures of Ley et al (1994). Alternatively, 3 Benzyloxy-2-ethyl-estra-1,3,5(10)-triene-17-one was prepared starting from (C2-3) by reduction of the acyl function which was achieved by reaction with Pd/C and H 2 [Gonzalez et al (1982)], subse quent benzylation of the 3-hydroxy function, deprotection of the C17 hydroxy function and TPAP 5 oxidation. Detailed Synthesis 3-Benzyloxy-2-ethyl-estra-1,3,5(10)-triene-17p-ol (C2-7): To benzyl protected acyl ketone (C2-4) (765 g, 1.71 mol) was added diethylene glycol (1900 10 ml), KOH (5.14 mol) and H 2

NNH

2

*H

2 0. The mixture was heated to 120-140'C overnight. A Dean Stark trap was placed and water and H 2

NNH

2

*H

2 0 were removed by distillation by heating the re action mixture to 190'C. After NMR analysis revealed complete conversion, the mixture was cooled to 50'C and water (3 I) was added. The mixture became very thick and unstirrable. The dissolved part was poured in a mixture of water (15 I) and EtOAc (5 I) and the sticky oil was first dissolved in 15 EtOAc (5 I) and then added to the mixture. The layers were separated and the organic layer was washed with water and concentrated to give (C2-7) (543 g, 81%) as orange / yellow oil which solidi fied upon standing. 3-Benzyloxy-2-ethyl-estra-1,3,5(10)-triene-17one (V-C2-C). 20 Alcohol (C2-7) (433 g, 1.39 mol) and powdered 4A molsieves (695 g, 500 mg/ mmol) in DCM (2.7 I) were cooled with an ice bath and TPAP (19.5 g, 55.6 mmol, 4 mol%) was added. NMO (2.09 mol) was added under ice/water cooling. After 3 h the reaction mixture was filtered over SiO 2 (DCM) and all fractions before the black fraction (TPAP) were collected. The DCM was concen trated to give ketone (V-C2-C) (465 g, 86%) as a yellow solid. 25 3-Benzyloxy-2-ethoxy-estra-1,3,5(10)-triene-17one (V-C2-D) 3-Benzyloxy-2-(2-methoxy-ethoxy)-estra-1,3,5(10)-triene-17one (V-C2-E) In the first step, the 2-hydroxy function of 3-Benzyloxy-estra-1,3,5(10)-triene-2,17p-diol (C2 A) was alkylated using ethylsulfate and LiOH or methoxyethanol under Mitsunobu conditions. Sub 30 sequently, the alcohol was oxidated with TPAP and NMO to the corresponding estron derivative. Detailed Synthesis 3-Benzyloxy-2-ethoxy-estra-1,3,5(10)-triene-17p-ol (C2-8) Intermediate (V-C2-A) (15.0 g, 39.68 mmol) was dissolved in THF (250 ml), under N 2 atmos 35 phere. LiOH (47.62 mmol) and Et 2

SO

4 (43.65 mmol) were added. The mixture was heated at 55 0 C for 5h, then cooled to RT and stirred for 48h. The mixture was concentrated in vacuo. DCM was added and the organic layer was washed with water and brine, dried over Na 2

SO

4 and concen trated in vacuo yielding 21.7 g of a greenish semi-solid. The mixture was dissolved in THF under N 2 atmosphere. LiOH (0.8 g) and Et 2

SO

4 (2.0 ml) were added. The mixture was heated to reflux and WO 2006/125800 PCT/EP2006/062587 87 refluxed over the weekend. The mixture was concentrated in vacuo. DCM was added and the or ganic layer was washed with water and brine, dried over Na 2

SO

4 and concentrated in vacuo to af ford 16.7 g (41.07 mmol, quant.) of brown oil. Pentane was added and the formed solid was filtered yielding 13.5 g (C2-8) (84%) as a white solid. 5 3-Benzvloxy-2-(2-methoxvethoxy)-estra-1,3,5(10)-triene-17p-ol (C2-9) Intermediate (V-C2-A) (15.0 g, 39.68 mmol), PPh 3 (79.37 mmol) and methoxyethanol (79.37 mmol) were suspended in DCM (500 ml) and cooled in an ice / water bath, under N 2 atmosphere. DIAD (79.37 mmol) was added drop wise in 1h at below 5*C. After addition a clear solution was 10 formed which was warmed to RT overnight. The solution was concentrated in vacuo yielding 58.8 g thick brown oil. Purification via column chromatography (SiO 2 , eluens DCM to 1% MeOH in DCM) yielded 34 g of thick oil. A second purification via column chromatography was done (SiO 2 , eluens 10% EtOAc to 50% EtOAc in heptan). Two fractions were collected, 7.61 g (44%) of pure product and 5.3 g which was purified via column chromatography yielding 3.1 g (18%). Both fractions were 15 mixed yielding 10.8 g (C2-9) (62%) as white powder. 3-Benzvloxy-2-ethoxy-estra-1,3,5(10)-triene-17one (V-C2-D) Compound (V-C2-D) (11.8 g, 29.6 mmol, 89%) was obtained as yellow solid from alcohol (C2-8) (13.5 g, 33.25 mmol) according to the procedure described for (V-C2-B). 20 3-Benzvloxy-2-(2-methoxy-ethoxy)-estra-1,3,5(10)-triene-17one (V-C2-E) Compound (V-C2-E) (11.6 g, 26.8 mmol) as white solid was obtained from alcohol (C2-9) (10.8 g, 24.54 mmol) according to the procedure described for (V-C2-B). 25 3-Benzyloxy-2-(2-methoxy-ethyl)-estra-1,3,5(10)-triene-17one (V-C2-F) Building Block V-C2-F was prepared starting from intermediate 2-Acetyl-3-benzyloxy-estra 1,3,5(10)-triene-17p-ol 17-acetate (C2-4). 2-Acetyl-3-benzvloxy-estra-1,3,5(10)-triene-17p-ol (C2-10) 30 Compound (C2-4) (119 g, 266 mmol) was dissolved in a mixture of THF (500 ml) and MeOH (500 ml) under N 2 atmosphere. A solution of KOH (1.06 mol) in water (1 1) was added. The reaction mixture was stirred at 75*C for 16h. After cooling to RT the pH of the mixture was adjusted to 4 us ing HAc. After dilution with water, the aqueous layer was separated. The organic layer was washed with brine, dried over Na 2

SO

4 , concentrated in vacuo, stripped with toluene and again dried in 35 vacuo yielding compound (C2-10) (70.0 g, 173.0 mmol, 65 %) as a yellow syrup. 3-Benzvloxy-2-(2-methoxy-1 -oxo-ethyl)-estra-13,5(1 0)-triene-1 7p-ol (C2-1 1) Compound C2-10 (70 g, 173 mmol) was suspended in diethyl ether (2 I) and bromine (363 mmol) was added dropwise at 0*C under N 2 atmosphere. The reaction mixture was stirred at ambi- WO 2006/125800 PCT/EP2006/062587 88 ent temperature for 14h. The solvent was removed in vacuo and the residue suspended in MeOH. Sodium methoxide (173 mmol) was added and the reaction mixture stirred at RT for 72h. This was poured into water, acidified with conc. aq. HCI and the water layer extracted with DCM. The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. Via column chroma 5 tography (Si0 2 , heptane/EtOAc 2/1 to 0/100 stepwise) compound C2-11 (14.3 g, 32.9 mmol, 19 %) was isolated. 3-Hydroxy-2-(2-methoxy-ethyl)-estra-1,3,5(10)-triene-17p-ol (C2-12) Palladium on charcoal (10%, 15 g) was suspended in water (175 ml) under N 2 atmosphere 10 and added to a solution of compound C2-11 (14.3 g, 32.9 mmol) in THF (175 ml) and t-butanol (175 ml). H 2 at ambient pressure was applied and the reaction mixture was stirred at ambient tem perature for 80h. The reaction mixture was filtered over Celite and the filter cake was washed with ethanol. The filtrate was concentrated in vacuo yielding crude compound C2-12 (8.3 g, 25.1 mmol, 77 %). After purification by column chromatography (Si0 2 , heptane/EtOAc = 3/1 to 1/2 stepwise) 15 pure C2-12 (3.6 g, 10.89 mmol, 33 %) was isolated. 3-Benzvloxy-2-(2-methoxy-ethyl)-estra-1,3,5(10)-triene-17p-ol (C2-13) Compound C2-12 (3.6 g, 10.89 mmol) was dissolved in acetone (30 ml) under N 2 atmos phere. Subsequently, benzylbromide (21.78 mol), anhydrous K 2 C0 3 (21.78 mmol) and 18-crown-6 20 (290 mg, 1.09 mmol) were added. The reaction mixture was refluxed for 24h (65*C external) and allowed to cool to RT. The mixture was poured into water (150 ml) and stirred for 1h. The water layer was separated and extracted with toluene. The combined organic layers were washed with brine, dried over Na 2

SO

4 and evaporated in vacuo leaving compound C2-113 (4.92 g, max. 10.89 mmol, quant.) as a yellowish solid. 25 3-Benzvloxy-2-(2-methoxy-ethyl)-estra-1,3,5(10)-triene-17-one (V-C2-F) Compound V-C2-F (3.43 g, 8.19 mmol, 70 %) was obtained as a pale solid from alcohol C2 13 (4.92 g, max. 10.89 mmol) according to the procedure described for (V-C2-B). 30 3-Benzyloxy-2-propyl-estra-1,3,5(10)-triene-17one (V-C2-G): 3-Benzyloxy-2-propyl-estra-1,3,5(10)-triene-17one was prepared starting from estradiol by introduction of the propionate side chain in C2 position as described by Rao et al. (2002) using a Fries rearrangement. Then the keto function is reduced to obtain the propyl side chain by reaction with Pd/C and H 2 [Gonzalez et al (1982)]. The subsequent oxidation of the C17 hydroxyl function 35 was achieved by TPAP oxidation using the procedures of Ley et al. (1994). Detailed Synthesis Estra-13,5(1 0)-triene-3,17p-diol di propionic acid ester (C2-14): WO 2006/125800 PCT/EP2006/062587 89 Estradiol (200 g, 0.734 mol) was dissolved in pyridine (2 I) under N 2 atmosphere. Propionic anhydride (344 g, 2.64 mol) was added. The reaction mixture was stirred at ambient temperature until the reaction was completed. The reaction mixture was cooled on an ice-water bath, quenched with MeOH (250 ml) and stirred at ambient temperature for 1%/ h. The mixture was concentrated in 5 vacuo and the residue was dissolved in toluene. The organic layer was separated, washed with water, 10% aqueous citric acid, sat. aq. NaHCO 3 and dried over Na 2

SO

4 . The organic layer was concentrated in vacuo and the residue was stripped with toluene, yielding compound C2-14 (272 g, 0.708 mol, 96 %) as a white solid. 10 Propionic acid 3-hydroxy-2-propionyl-estra-1,3,5(10)-triene-17-vI ester (C2-15): Compound C2-14 (272 g, 0.708 mol) was dissolved in DCM (10 L) under N 2 atmosphere. Zirconium chloride (758 g, 3.25 mol) was added, which resulted in a yellow suspension. The mix ture was stirred at ambient temperature until the conversion was completed. The reaction mixture was cooled to 3*C before 200 g ice was added in batches. Water (2 L) was added and the mixture 15 was stirred at 4*C for 1 hr. Then an additional amount of water (5 L) was added. The aqueous layer was separated and extracted with DCM. The combined organic layers were filtered over Na 2

SO

4 and concentrated in vacuo. The residue was stripped with toluene leaving a green residue. The residue was dissolved in DCM and filtered over SiO 2 leaving compound C2-15 (255 g, 0.663 mol, 94 %) as an orange solid. 20 Propionic acid 3-hydroxy-2-propyl-estra-1,3,5(10)-triene-17-vI ester (C2-16): Pd (10%) on charcoal (120 g) was suspended in water (800 ml) under N 2 atmosphere. t Butanol (800 ml) and a solution of compound C2-15 (115 g, 0.299 mol) in THF (800 ml) were added. The mixture was applied to H 2 and stirred at ambient temperature until the reaction was 25 completed. The mixture was filtered over Celite (2x) and the filter cake was washed with THF. The filtrate was concentrated in vacuo yielding compound C2-16 (107 g, 0.289 mol, 97%) as gray solid. Propionic acid 3-benzvloxy-2-propyl-estra-1,3,5(10)-triene-17-vI ester (C2-17): Compound C2-116 (238 g, 0.642 mol) was dissolved in acetone (1.5 I) under N 2 atmosphere. 30 Subsequently, benzylbromide (0.7 mol), anhydrous K 2 C0 3 (0.723 mol) and 18-crown-6 (0.038 mol) were added. The reaction mixture was refluxed overnight. Additional amounts of K 2 C0 3 (0.181 mol + 0.362 mol) and benzylbromide (0.084 mol) were added. After refluxing the mixture for additional 64 h, the mixture was allowed to cool to 30*C and poured into water. The mixture was extracted with toluene. The organic layers were combined and concentrated in vacuo. The residue was 35 stripped with toluene leaving compound C2-17 (335 g, max. 0.642 mol) as a wax like solid. 3-Benzvloxy-2-propyl-estra-1,3,5(10)-triene-17p-ol (C2-18): Compound C2-17 (69.9 g, max. 134 mmol) was dissolved in a mixture of THF (600 ml) and MeOH (600 ml) under N 2 atmosphere. A solution of KOH (34.4 g, 613 mmol) in water (600 ml) was WO 2006/125800 PCT/EP2006/062587 90 added. The reaction mixture was stirred at 55*C for 3h. MeOH was removed in vacuo from the mix ture. DCM (400 ml) was added and the pH of the mixture was adjusted to 1 using 3M HCI. The aqueous layer was separated and extracted with DCM (2x 200 ml). The organic layers were com bined, washed with sat aq NaHCO 3 (200 ml) and dried over Na 2

SO

4 . The organic layer was con 5 centrated in vacuo yielding compound C2-18 (61.6 g, 152 mmol, 88 %) as a yellow syrup after col umn chromatography (Si0 2 , DCM/heptane = 85/15). 3-Benzvloxy-2-propyl-estra-1,3,5(10)-triene-17-one (V-C2-G): Compound V-C2-G (57.6 g, 143 mmol, 94 %) was obtained as a pale solid from alcohol C2 10 18 (61.6 g, 152 mmol) according to the procedure described for (V-C2-B). 3-Hydroxy-2-propyl-estra-1,3,5(10)-triene-17-one (V-C2-G-a): Compound V-C2-G (1.10 g, 2.73 mmol) was dissolved in THF (15 ml) under N 2 atmosphere. A suspension of palladium on charcoal (10 %, 130 mg) in THF (10 ml) was added. H 2 was applied 15 at ambient pressure and the reaction mixture was stirred at RT for 3 d. The reaction mixture was filtered over Celite and the filter cake was washed with THF (20 ml). The filtrate was concentrated in vacuo yielding compound (V-C2-G-a) (240 mg, 0.768 mmol, 28 %) after column chromatography (Si0 2 , DCM). 20 11. 15, 16-unsaturated and C2 substituted Estrone derivatives of formula (X) (Step B) The estrone of general formula V was converted into the corresponding 15, 16 unsaturated derivative by the 4-step reaction as depicted in SCHEME 1 according to Nambara 1976: After pro 25 tection of the C17 keto function as acetal (ethylene glycol, TEOF and p-TosOH in toluene, work-up with water and TEA), the acetal was brominated (with pyridinium perbromate and ethylene glycol in DME, work-up with Na 2

S

2 0 3 ). Subsequently, HBr was eliminated by reaction with K-0-tert-butyl in DMSO. Finally, the deprotection of the acetal was achieved with p-TosOH in DME and water. 30 The following intermediates were prepared according to this procedure: 3-Benzvloxy-2-methoxy-estra-1,3,5(10),15-tetraene-17-one (X-C2-B) 3-Benzvloxy-2-ethyl-estra-1,3,5(10),15-tetraene-17-one (X-C2-C) 3-Benzvloxy-2-ethoxy-estra-1,3,5(10),15-tetraene-17-one (X-C2-D) 35 3-Benzvloxy-2-methoxy-ethoxy-estra-1,3,5(10),15-tetraene-17-one (X-C2-E) 3-Benzvloxy-2-methoxy-ethyl-estra-1,3,5(10),15-tetraene-17-one (X-C2-F) 3-Benzvloxy-2-propyl-ethoxy-estra-1,3,5(10),15-tetraene-17-one (X-C2-G) WO 2006/125800 PCT/EP2006/062587 91 Ill. Introduction of the basic side chain in C15 position The detailed synthesis of the following intermediates, wherein R represents H, is fully dis closed within international patent application WO 2005/47303, which is incorporated by reference 5 herein. For intermediates with R is different from H, detailed synthesis is given for exemplary compounds. Illa. The optionally 2-substituted ketal derivative of the Estron-15a-vl-carbaldehyde of formula X111-0 0 0 H R14 H (XIII-O) PGs 0 H H O O H 10 The protected aldehyde intermediate of formula X111-0 with PG = CH 3 (Xlllb) or PG Benzyl (XIllc) can be prepared according to a procedure depicted within the following scheme 2: SCHEME 2 0 0 HH R1- KCN/H 2 0 - 4RH4HO OH PGO PG H ON pTosOH 0GI G 0 C (X) (XI) O0 0 1. Dibal-H O 2. AcOH/H 2 0 R14 - H 3. NaHCO3 R14 H

PGI

0 H H CN PG H H O H (XII)(X111-0) 15 The optionally 2-substituted 15,16-unsaturated estrone of formula (X) was converted into the corresponding cyano-estrone (XI) by a cyanide Michael addition at the D-ring. The nitrile was intro duced in the beta configuration as was proven by 2D-NMR. Epimerization of this stereocenter had been accomplished in a following step. First the ketone functionality was protected as the acetal (XII), followed by conversion of the nitrile to the corresponding aldehyde (XIII-0) by the addition of 20 DIBAH to the nitrile and the consecutive hydrolysis of the imine product. At this stage the epimeri zation took place for about 90% (2D-NMR). Consecutive washing of the mixture with aqueous bi carbonate gave the a-isomer with a d.e : 98%.

WO 2006/125800 PCT/EP2006/062587 92 Illb. Optionally 2-substituted compounds of formula IV: Estron-15-vl-Co-C 5 -alkyl-carboxylic acid Acid building block IV-0: (n = 0) 0 H H PG OH o o 5 The individual steps in the synthesis of acid building block of the formula IV-Ob are depicted in the following scheme 3. SCHEME 3 O0 0 1. KMnO, H R14H 2. HCI/H 2 0 R14 PG H N NPG OH 0 H00 (XIII-O) (IV-O) 10 The ketal derivative of the optionally 2-substituted 17-oxo-estra-1,3,5(10)-trien-15a-yl carbaldehyde of formula X111-0 is oxidized to the corresponding carboxylic acid and converted into the unprotected 15a-substituted estrone derivative of formula IV-0. Acid building block IV-1: (n = 1): 0 R14 H HO OH (Iv-1) H H-: O PG O 15 0 The acid building block IV-1 may be synthesized via two different routes. The individual steps of the first synthesis route of acid building block IV-1 are depicted in the following scheme 4. The same kind of procedure can be applied for n = 2 and for other side chains within the PG posi tion. 20 SCHEME 4 WO 2006/125800 PCT/EP2006/062587 93 0 0 H MeOCH 2 P(Ph 3 )C R14 H R14 .n-BuLi PGH H PGO 0 H O (XIII-O) (XXXIV) 0 0 1. KMn04 R14 H 2. HCI/H 2 0 R14 H

HCIH

2 0 I HN PGO H H PGO 0) 0 (XXX111-1) (IV-1) The ketal derivative of the 17-oxo-estra-1,3,5(10)-trien-15a-yl-carbaldehyde of formula XII1-0 is converted into the methyl enol ether of the formula XXXIV via a Wittig reaction with 5 MeOCH 2 LiP(Ph) 3 . Hydrolysis with HCI(q) delivered the unprotected acetaldehyde derivative XXXIII 1. The acetaldehyde derivative is then further oxidized to the corresponding carboxylic acid IV-1. Alternative synthesis route for the acid building block IV-1: (n = 1): IV-1 b: (n = 1 and PG = CH): 3-Methoxy-1 7-oxo-estra-13,5(1 0)-trien-1 5a-yl-acetic acid 10 Alternatively, compound IV-1 b can be prepared directly from the enone derivative of formula X according to the following synthesis scheme 5: SCHEME 5 o o R14 H MeCO 2

CH

2

CO

2 Me R14 H O NaH 0_ 0 o 4 0 (Xb) 0 (XXXVlb) R14 H 1.NaOH .. O 2. AcOH 0 OH (IV-1b) 15 A Michael addition of the dimethylmalonate-anion to the enone derivative delivered the diester XXXVIb, which was converted into the acid building block of formula IV-b by alkaline ester hydrolysis and decarboxylation in refluxing acetic acid.

WO 2006/125800 PCT/EP2006/062587 94 Optionally 2-substituted acid building blocks IVp-2, IVp-3, IVp-4, IVp-5, IV-6 (n = 2, 3, 4, 5, 6): IVp-3b (n = 3 and PG = CH): 4-(3-Methoxy-17-oxo-estra-1,3,5(10)-trien-15p-vl)-butyric acid O (IVp-3b) H H OH The individual steps in the synthesis of acid building block of the formula IVp-3b are depicted 5 in the following scheme 6. The same kind of procedure can be applied for n = 4, 5, or 6 and for other alkyl side chains within the R 1 position using the appropriate BrMg-C 5

-C

7 -alkoxy-THP as Grignard Reagent. Furthermore, this reaction scheme also delivers the estrone-alcohol building block in form of the intermediate of formula XXXIp-4b. 10 SCHEME 6 0 00 Br OH _ Br O O 0 B0 BrMg O 0 0 Br""'- 0 HR/4yH R 14 H (XXX-4b-THP) H HH 0 0 0Xb 0 H SOH (IVp-3b) 0 (XXXIp-4b) 4-Bromo-butanol-THP ether was prepared by adding HBr solution to refluxing THF. The re sulting bromide was dissolved in DCM, p-TosOH and DHP were added at 0*C to give the protected 15 alcohol. This was filtered over Si0 2 and further purified by column chromatography, yielding 9.3% over 2 steps. The protected alcohol was dissolved in THF and added to activated magnesium, and the resulting Grignard reagent added to Cul 2 in HMPA. The 15, 16-unsaturated Estrone derivative of formula Xb, dissolved in dry THF and TMSCI, was added at -40±5*C. Subsequently, after hy drolysis of the silyl ether, the resulting compound XXX-4b-THP was deprotected with p 20 TosOH/MeOH to give the alcohol derivative XXXI-4b, which was converted, without purification, into the free acid IV-3b by a Jones oxidation. The oil was purified by column chromatography, yield ing the free acid of formula IV-3b in 30% yield over three steps.

WO 2006/125800 PCT/EP2006/062587 95 Acid building blocks IVp-2 (n = 2 and PG = H, CH 3 or benzyl): optionally 2-substituted 3-(3 Benzvloxy/Methoxy/Hydroxy-17-oxo-estra-1,3,5(10)-trien-15p-vl)-propanoic acid R14 H H H PG,0 IVp-2 HO 5 The optionally 2-substituted carboxylic acid IVp-2 can be prepared by oxidation of the alco hol derivative of formula XXXIp-3b or XXXIp-3c according to the preparation of the carboxylic acid IVp-3b (see section for the preparation of the alcohol derivatives below for synthesis of XXXIp-3b and XXXIp-3c) and optionally subsequent debenzylation of the C3 hydroxy function. 10 Acid building block IVp-3c: Optionally 2-substituted 4-(3-Benzvloxy-17-oxo-estra-1,3,5(10)-trien 15p-vl)-butyric acid H R H (1Vp-3c) OH The synthesis of acid building block of the formula IVp-3c is performed according to any of the procedures depicted in the following schemes 7A, 7B and 7C. Furthermore, reaction scheme 15 7A also delivers the estrone-alcohol building block in form of the intermediate of formula XXXIp-4c. The same kind of procedure can be applied for n = 4, 5, or 6 and for other alkylaryl substitutents within the R 1 position using the appropriate BrMg-Cs-Cr-alkoxy-THP as Grignard Reagent. SCHEME 7A 0 0 H BrMg O O R14 - H .R 1 4 H O O H H 0 O (xc) 1 (XXX-4c-THP) O 0 H H 14 OH OH 0 20 (IV13-3c) 0(XXXII3-4c) WO 2006/125800 PCT/EP2006/062587 96 4-Bromo-butanol-THP ether was prepared by adding HBr solution to refluxing THF. The re sulting bromide was dissolved in DCM, p-TosOH and DHP were added at 0*C to give the protected alcohol. This was filtered over Si0 2 and further purified by column chromatography, yielding 9.3% over 2 steps. The protected alcohol was dissolved in THF and added to the activated magnesium, 5 and the resulting Grignard reagent added to Cul 2 in HMPA. The 15, 16-unsaturated Estrone deriva tive of formula Xc (preferably with R = H), dissolved in dry THF and TMSCI, was added at 40±5*C. Subsequently, the resulting compound XXX-4c-THP was deprotected with p TosOH/MeOH to give XXXIp-4c in 47% over 2 steps, which was converted, without purification, into the free acid IVp-3c by a Jones oxidation in a yield of 96%. 10 SCHEME 7B 0 0 H BrMg H R14 H .R14H O O 0 0 (Xc) O (XXX-4c) R14 H O (IVp-3c) 0 The 15, 16-unsaturated Estrone derivative of formula Xc (preferably with R 1 4 = Ethyl, n Propyl or Methoxyethyl) was subjected to a 1,4 addition using a freshly prepared Gringard Re 15 agent. Subsequently, the resulting compound XXX-4c was oxidized to the free acid IVp-3c (see also the reaction SCHEME 12). SCHEME 7C 0 0 -O HR4H 0 R14 BrMg H H 00 (Xc) (XXX-2c) R14 R14 O O H H O O

O

WO 2006/125800 PCT/EP2006/062587 97 SCHEME 7C, continued 0 H R144 (IM-3a) H H OH HO) The 15, 16-unsaturated Estrone derivative of formula Xc (preferably with R = Methoxy) was subjected to a 1,4 addition using a freshly prepared Gringard Reagent. Subsequently, the resulting 5 compound XXX-2c was reacted with with acrylic acid methyl ester using a Grubb 11 catalyst, known as olefin metathesis. After removal of the methyl group, the free acid (lVb-3a) is obtained by hydro genation and deprotection. Alternatively, the last two steps may be performed in reversed order. Detailed Synthesis for exemplary compounds 10 4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15 -yI)-butyric acid (IV1-(C2-B)-3a) 0 H (IVb-(C2-B)-3a) H H OH HO Compound (IVp-(C2-B)-3a) was prepared according to general procedure depicted in SCHEME 7C starting from compound (X-C2-B). 15 15p-Allyl-3-benzyloxy-2-methoxy-estra-1,3,5(10)-trien-17-one (XXXB-(C2-B)-2c): Under N 2 -atmosphere, LiCI (247 mmol) and Cul (247 mmol) were dissolved in THF (500 ml). The solution obtained was cooled to Tintem= -78*C, and allyl-MgBr (1 M in Et 2 O, 246 mmol) was added dropwise during 1.5 h. After stirring for 0.5 h, TMSCI (171 mmol) was added and the reac tion mixture was further stirred at Tintem= -78*C for 0.5 h. Then, a solution of (X-C2-B) (26.5 g, 68.2 20 mmol) in THF (250 ml) was added dropwise during 1.5 h. The reaction mixture was stirred at Tintem= -78*C for 1.5 h, after which it was allowed to warm to RT, quenched with sat. NH 4 CI (aq) (600 ml), and stirred at RT overnight. The reaction mixture was filtered over celite and the residue was washed with EtOAc (200 ml). The organic layer was isolated from the combined filtrates, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 1 N 25 HCI, 1N NH 4 0H (aq), brine, dried over Na 2

SO

4 , filtered, and concentrated in vacuo to yield (XXX (C2-B)-2c) (34.8 g, 98%). 4-(3-Benzyloxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15@-yl)-but-2-enoic acid methyl ester: Under N 2 -Atmosphere, in oven-dried glassware, Grubbs 11 catalyst (2.36 mmol) was added to 30 a solution of (XXX-(C2-B)-2c) (60.4 mmol) and methyl acrylate (150 mmol) in DCM (500 ml). The WO 2006/125800 PCT/EP2006/062587 98 mixture obtained was stirred at RT overnight, heated at Ttwem= 39 *C for 8 h, after which it was al lowed to cool to RT. The reaction mixture was evaporated to dryness to furnish 30.8 g resin, which was applied to SiO 2 (1500 ml) with DCM and eluted with a DCM:EtOAc gradient (99:1 to 90:10) to yield the desired compound (18.5 g, 63%) (Rf=O.1 (DCM)). This was dissolved in THF (250 ml) and 5 heated at reflux with activated charcoal (1 g) for 20 min. The mixture obtained was allowed to cool to RT, filtered and the filtrate was concentrated in vacuo. 4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-vl)-butyric acid methyl ester (Vl13 (C2-B)-3a-1) 10 A solution of 4-(3-Benzyloxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15@-yl)-but-2-enoic acid methyl ester (17.3 g, 2.36 mmol) in THF (440 ml) and MeOH (440 ml) was purged with H 2 (bal loon). Then Pd (10% on carbon, 50% H 2 0) (1.80 g) was added, and the mixture obtained was stirred under H 2 pressure for over night. The reaction mixture was filtered over two filter papers and concentrated in vacuo to yield the desired compound (Vllp-(C2-B)-3a-1) (13.8 g, 97%), which 15 represents a compound falling under the scope of the present invention. 4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyric acid (IVp-(C2-B)-3a) A solution of LiOH-H 2 0 (197 mmol) in H 2 0 (450 ml) was added to a solution of (Vllp-(C2-B) 3a-1) (34.5 mmol) in THF (450 ml) and the mixture obtained was stirred at RT overnight. The reac 20 tion mixture was concentrated in vacuo to remove THF and diluted with H 2 0. The mixture was washed with DCM, acidified with 1N HCI to pH 1 and extracted with DCM. The combined extracts were washed with brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo to yield (IVp-(C2-B) 3a) (11.7 g, 88%). 25 4-(3-Hydroxy-2-(2-methoxy-ethyl)-17-oxo-estra-1,3,5(10)-trien-150-yI)-butyric acid H (IVb-(C2-F)-3a) HO Compound (IVp-(C2-F)-3a) was prepared according to general procedure depicted in SCHEME 7C starting from compound (X-C2-F). 30 15-Allyl-3-(benzyloxy)-2-(2-methoxy-ethyl)-estra-1,3,5(10)-trien-17-one (XXXl-(C2-F)-2c): A flame dried flask was charged with Cul (1.38 mmol) and LiCI (1.38 mmol) under N 2 atmos phere. THF (5 ml) was added and stirred at ambient temperature until a clear green solution was obtained. After cooling the solution to -78*C, allylmagnesium bromide in EtO 2 (1.38 mmol) was added dropwise and stirred at -78*C for 1 h. Then TMSCI (1.38 mmol) was added in a single batch. 35 A solution of compound X-C2-F (192 mg, 0.46 mmol) in THF (5 ml) was added dropwise at -78*C.

WO 2006/125800 PCT/EP2006/062587 99 The reaction mixture was stirred at -78*C for 2h and the mixture was allowed to reach RT over night. The mixture was quenched with sat aq NH 4 CI (50 ml). The organic layer was separated and washed with aq. 1M HCI (25 ml), aq. 1M NH 4 0H (25 ml) and brine (25 ml). The combined organic layers were dried over NaSO 4 and concentrated in vacuo yielding compound (XXXp-(C2-F)-2c) 5 (220 mg, max. 0.46 mmol). Purification via SiO 2 (DMC/methanol = 100/0 to 98/2) delivered pure (XXXP-(C2-F)-2c) (56 mg, 0.122 mmol, 22 %). 4-(3-Benzvloxy-2-(2-methoxy-ethyl)-17-oxo-estra-1,3,5(10)-trien-15@-yl)-but-2-enoic acid ethyl ester: 10 Compound (XXXp-(C2-F)-2c) (46 mg, 0.10 mmol) was dissolved in DCM (5 ml) under N 2 at mosphere. Ethyl acrylate (0.135 mmol) and Grubbs 11 catalyst (0.01 mmol) were added. The reac tion mixture was stirred at ambient temperature for 18h. The reaction mixture was filtered over celite and concentrated in vacuo yielding the title compound (46 mg, 0.086 mmol, 85 %) after puri fication over SiO 2 (DCM/MeOH = 100/0 to 98/2). 15 4-(3-Hydroxy-2-(2-methoxy-ethyl)-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyric acid ethyl ester (Vllp-(C2-F)-3a-1) Palladium on charcoal (10%, 15 mg) was suspended in methanol (5 ml) under N 2 atmos phere. A solution of the previous compound (45 g, 0.085 mmol) in THF (5 ml) was added carefully. 20 H 2 at ambient pressure was applied and the reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was filtered over Celite and the filter cake was washed with THF (10 ml). The filtrate was concentrated in vacuo yielding compound (Vllp-(C2-F)-3a-1) (40 mg, max. 0.085 mmol), which also represents a compound falling under the scope of the present invention. 25 4-(3-Hydroxy-2-(2-methoxy-ethyl)-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyric acid (IVp-(C2-F)-3a) The previous compound (40 mg, max. 0.085 mmol) was dissolved in a mixture of THF (2 ml), water (2 ml) and LiOH-H 2 0 (0.45 mmol). The mixture was stirred at ambient temperature for 5h. THF was removed in vacuo and the residue diluted with water (5 ml). The alkaline layer was 30 washed with DCM (1x 10 ml) and the organic layer discarded. The water layer was acidified till pH 3 using aq. 1 M HCI and extracted with DCM (4x 25 ml). The combined organic layers were washed with brine (25 ml), dried over Na 2

SO

4 and concentrated in vacuo yielding compound (IVp-(C2-F) 3a) (26 mg, 0.063 mmol, 74 %) as pale solid. 35 The following further building blocks were prepared according to this procedure: 4-(3-Hydroxy-2-ethyl-1 7-oxo-estra-1,3,5(1 0)-trien-1 513-yl)-butyric acid (IVp-(C2-C)-3a) 4-(3-Hydroxy-2-propyl-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyric acid (IVp-(C2-G)-3a) WO 2006/125800 PCT/EP2006/062587 100 Optionally 2-substituted acid building block with a stereochemistry at C15: IVa-3a (n = 3 and PG = H): 4-(3-Hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-vl)-butyric acid 0 H R14 (IVax-3a) S H H 0 HO1 OH The individual steps in the synthesis of the optionally 2-substituted acid building block of the 5 formula IVa-3a are performed according to any of the procedures depicted in schemes 8A and 8B. Furthermore, reaction scheme 8A also delivers the still ketal-protected estrone-alcohol building block in form of the intermediate of formula XLIVa-1c. Debenzylation and deprotection delivers the estrone-alcohol )XXIXa-1a. 10 SCHEME 8A o 0 o 0 H H R14 R14 O/- H OON N -- OH (X111-Oc (XLIVa,-1c) 00 0 0 R14 H -- IR14HO H H (XLV) O (XLVI) 0 o 0 O 0 H H H H % H H OH HO O HO OH (XLVII) 0 O (XLVIIIa-3a) 0 H R14 I - - (IVa-3a) H H OH HO 0 Reduction of the aldehyde XIll-Oc with NaBH 4 (EtOH, 2h, RT) gave the alcohol XLIVa-1c, which was further treated with iodine, triphenylphosphine and imidazole to give the iodide XLV. 15 Subsequently, ethylacrylate was coupled to iodine XLV and gave compound XLVI after purification WO 2006/125800 PCT/EP2006/062587 101 by column chromatography. Reduction of compound XLVI was performed under H 2 atmosphere to give compound XLVII, which was transformed into the protected carboxylic acid building block XLVIIx-3a by saponification. The carboxylic acid IVa-3a was obtained by deprotection. 5 SCHEME 8B 0 OH R14H CMg R14 H H HH 0 O (Xc) O 0 H -O H R14 0 R14 (XXX-2c) 0 0 0 H R14 - HR H~ H~. HO - HOH- OH 0o HO O(IVa-3a)0 (VIIa-3a) 0 The allyl group was introduced into the optionally C2 substituted, 15, 16-unsaturated Estrone derivative of formula Xc by reaction with allylmagnesium chloride or bromide, followed by an oxy cope rearrangement catalysed by KH and 18-Crown-6. Subsequently, the resulting compound 10 XXX-2c was reacted with acrylic acid methyl ester using a Grubb 11 catalyst, known as olefin me tathesis. The free acid (IVa-3a) is obtained by hydrogenation, deprotection, and, in the last step, hydrolysation of the methyl ester with LiOH. Detailed Synthesis for 4-(2-Ethoxy-3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-yl)-butyric acid 0 H O (IVax-(C2-D)-3a) H H HO 15

OH

WO 2006/125800 PCT/EP2006/062587 102 17-Allyl-3-(benzyloxy)-2-ethoxy-estra-1,3,5(1 0)-trien-1 7-ol Allylmagnesiumchloride (1.7 M in THF, 48.39 mmol) was added dropwise to a solution of ke tone X-C2-D (6.5 g, 16.1 mmol) in THF (200 ml) under N 2 atmosphere at 0 0 C. After stirring for 4h at 0-5 0 C, the solution was poured into sat aq NH 4 CI. The water layer was extracted with DCM. The 5 combined organic layers were washed with sat NaHCO 3 , dried over Na 2

SO

4 and concentrated in vacuo yielding 7.8 g (100%) as thick yellow oil. 15a-Allyl-3-benzyloxy-2-ethoxy-estra-1,3,5(10)-trien-17-one (XXX-(C2-D)-2c) KH 30% in oil (89.98 mmol) was suspended in THF (50 ml), under N 2 atmosphere. 17-Allyl 10 3-(benzyloxy)-2-ethoxy-estra-1,3,5(10)-trien-17-ol (7.7 g, 17.30 mmol) and 18-Crown-6 (88.25 mmol) were dissolved in THF (200 ml) and added dropwise in 40 min. The mixture was stirred for 3 h at RT. The mixture was carefully poured into IPA via canula. The mixture was poured into aq. sat.

NH

4 CI. The water layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. Purification via filtration over Silica (eluens 15 heptan to 40% DCM in heptan) provided 4.2 g (9.51 mmol, 55%) of (XXX-(C2-D)-2c). 4-(3-Benzyloxy-2-ethoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-vl) but-2-enoic acid methyl ester Substrate (XXX-(C2-D)-2c) (4.2 g, 9.51 mmol) was dissolved in DCM (100 ml) under N 2 at mosphere. Methylacrylate (23.76 mmol) and Grubbs (11) catalyst (0.380 mmol) were added. The 20 mixture was refluxed overnight. The mixture was concentrated in vacuo to afford 4.7 g of dark brown solid. Purification via column chromatography yielded 3.17 g (66%) of a brown semi-solid. 4-(3-Hydroxy-2-ethoxy-17-oxo-estra-1,3,5(10)-trien-15a-vl) butyric acid methyl ester (Vla (C2-D)-3a) 25 4-(3-Benzyloxy-2-ethoxy-17-oxo-estra-1,3,5(10)-trien-15a-yl) but-2-enoic acid methyl ester (3.17 g, 6.30 mmol) was dissolved in THF (80 ml) and MeOH (80 ml). Pd/C 10% (50% in water, 0.3 g) was added. The mixture was stirred at 1 atm H 2 (balloon) at RT for 48 h. The mixture was filtered over Celite. The filter cake was rinsed with MeOH and the filtrate was concentrated in vacuo to provide 2.8 g (6.72 mmol, 100%) of a greenish solid. 30 4-(2-Ethoxy-3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15a-yl)-butyric acid (IVa-(C2-D)-3a) Methylester (Vlla-(C2-D)-3a) (2.8 g, 6.72 mmol) was dissolved in THF (80 ml). LiOH (39.86 mmol) was dissolved in water (80 ml) and added in one portion. The solution was stirred at RT overnight. The solution was concentrated in vacuo and water (350 ml) was added. The water layer 35 was washed with DCM (3 x 200 ml) and acidified to pH 1 with 2N HCI and extracted DCM. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated in vacuo to afford 1.84 g (68%) of white foam, LC-MS purity of 97-100%.

WO 2006/125800 PCT/EP2006/062587 103 'H-NMR (CDCl 3 , 300 MHz): 5 0.95 (s,3H), 1.25 (m, 2H), 1.4 (t, 3H), 1.5 (m, 3H), 1.60-2.1 (m, 6H), 2.1-2.45 (m, 6H), 2.80 (m, 3H), 4.1 (q, 2H), 6.65 (s, 1H), 6.80 (s, 1H) 4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15a-yl)-butyric acid (lVa-(C2-B)-3a) and 4-(3 5 Hydroxy-2-(2-methoxy-ethoxy)-17-oxo-estra-1,3,5(10)-trien-15a-yl)-butyric acid (lVa-(C2-E)-3a) 0 0 H H HO HO (lVc-(C2-B)-3a) OH (lVac-(C2-E)-3a) OH These two intermediates were synthesized accordingly from ketones X-C2-B and X-C2-E, respectively. 10 4-(3-Hydroxy-2-(2-methoxy-ethoxy)-17-oxo-estra-1,3,5(10)-trien-15a-vl)-butyric acid (IVa (C2-E)-3a) 'H-NMR (CDCl 3 , 300 MHz): 50.95 (s, 3H), 1.3 (t, 2H), 1.5 (m, 3H), 1.6-2.1 (m, 6H), 2.1-2.4 (m, 6H), 2.8 (m, 3H), 3.4 (s, 3H), 3.7 (t, 2H), 4.1 (m, 2H), 6.62 (s, 1H), 6.9 (s, 1H) 15 4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15a-vl)-butyric acid (lVa-(C2-B)-3a) 'H-NMR (shifts in ppm): 0.96-1.04 (s, 3H), 1.20-2.48 (m, 16H), 2.70-2.94 (m, 3H), 3.80-3.92 (s, 3H), 6.60-6.68 (s, 1H), 6.76-6.80 (s, 1H). 20 Illc. Compounds of formula XXXI (alcohol derivatives): Optionally 2-substituted 15-hydroxy-Cl-C 6 : alkyl-Estron Alcohol building block XXXla-1 (n 1) O H R14 3 . (XXXlCa) PG OH 25 The synthesis of the alcohol derivatives )XXIa-1a (PG =R = H), )XXIa-1b (PG R=

CH

3 ), and XXXla-1c (PG = R1 = benzyl) is depicted in the following scheme 9: WO 2006/125800 PCT/EP2006/062587 104 SCHEME 9 0/a 0 0 H H

R

14

R

1 4 H H H0H R10 H 0 R O OH (X111-0) (XXXia-1) XIll-Ob: R 1

=CH

3 0 XXXIa-1b: Ri=CH 3 XIll-Oc: R 1 =CH XXXIa-1c: Ri=CH 2 _ 0 0

R

1 4 H R 1 4 H HOH OH O OHXIAC HO OH (XX~i-1c)(XXXicAa) Reduction of the aldehydes XIII-Ob or XIII-Oc using NaBH 4 followed by ketal hydrolysis gave the corresponding alcohols XXXla-1b and XXXla-11c. The alcohol XXXla-1c was debenzylated to 5 give )XXIa-1a using Pd/C and a 5 bar hydrogen atmosphere. Alcohol building blocks XXXI-3c and XXXI-3a (n = 3) and XXXI-5c and XXXI-5a (n = 5) with PG=Rl=benzvl or PG=R'=H): 0 0 R14__ R14 PG PG OH O C OH 0 XXXI-3 XXXI-5 10 The synthesis of the optionally 2-substituted alcohol building blocks of formula XXXI-3 and XXXI-5 is depicted in the following scheme 10. SCHEME 10 0 0 R14MgCI R14 HH HH XXXV-3c (n1l) (Xc) XXXV-5c (n3) O 0 O 0 R14 H R14 0 0 OH XXXII-3c (n=) 15 XXXI I-5c (n=3) WO 2006/125800 PCT/EP2006/062587 105 SCHEME 10, continued O O , R14 R14H H H ( nH H ( n O O HO O XXXI-3c (n=1) XXXI-3a (n=1) XXXI-5c (n=3) XXXI-5a (n=3) The 15, 16-unsaturated Estrone derivative of formula Xc (preferably with R 14 H, Ethyl, n 5 Propyl or Methoxyethyl) was subjected to a 1,4 addition using a freshly prepared Gringard Reagent (allylmagnesiumchloride or pentenylmagnesiumchloride) delivering compound XXXV. After protection of the ketone functionality in C17 as ketal, the alkenyl side chain was hydroborated and subsequently oxidized to provide compound XXXII. After deprotection of the C17 keto function by treatment with pTosOH, the benzyl function is optionally cleaved off to deliver the alcohol building 10 blocks XXXI- 3 and XXXI-5, respectively. Alcohol building blocks XXXI-4b, XXXI-5b, XXXI-6b (n = 4, 5, 6): 15p-(4-Hydroxy-C 4

-C

6 -alkyl)-3-methoxy-estra-1,3,5(1 0)-trien-1 7-one: 0 R14 H (XXXI-4b) (XXXI-5b) H H( ) (XXXI-6b) OH 15 The general synthesis of the alcohol building block of formula XXXI-4/5/6b is depicted in the following scheme 11. SCHEME 11 O O(XXX-4b-THP) (XX-5b-THP) H H (XXX-6b-THP) BrMg-(CH 2 )n= 6 -O-THP R14 H H H H O O (Xb) R14 - H .(XXXI-4b) (XXXI-5b) H H OH (XXXI-6b) O n=1-3 20 WO 2006/125800 PCT/EP2006/062587 106 General Procedure Magnesium (3-10eq) is added in a dry three-neck flask under N 2 atmosphere and activated by iodine. The bromo compound (2-6.5 eq) dissolved in dry THF is added dropwise to the magne sium. The reaction mixture is allowed to react for 1-2 h at RT or reflux. The solution is transferred to 5 dry three-neck flask containing Cul (0.06-0.7 eq) and DMPU or HMPA (2-7 eq) in dry THF cooled to -40 *C. The resulting mixture is stirred for 30 min at -40 *C after which a mixture of 15,16 unsaturated estron derivative of formula X (1 eq) and TMSCI (2-2.5 eq) dissolved in THF is added dropwise. After complete addition the mixture is allowed to reach RT. Then NH 4 CI-solution is added, the layers are separated and the aqueous phase is extracted with EtOAc (3x). The com 10 bined organic phases are dried over Na 2

SO

4 and the solvent is evaporated. The crude product is dissolved in methanol and K 2 C0 3 (1eq) is added to hydrolyse the silyl ether. After complete hy drolysis water is added and most of the methanol is evaporated. The mixture is diluted with EtOAc, the layers are separated and the water layer is extracted with EtOAc. The combined organic layers are dried over Na 2

SO

4 and the solvent is evaporated. The resulting product of general formula XXX 15 is then further worked-up to give the alcohol of general formula XXXI. Alcohol building block XXXI-4 (n = 4) with PG = Benzyl or H 0 R14 yXXX-4 PGIIIO) O0H The detailed synthesis of these compounds is already displayed within the section for the 20 synthesis of acid building block of the formula IV-3c above. The 3-hydroxy-derivative can be ob tained by debenzylation of the XXXI-4c compound. Alcohol building blocks X)XI-6c and XXXI-6a (n = 6): 0 (XXXI-6) PGs 25 The detailed synthesis of these compounds is performed according to the general procedure displayed in SCHEME 11 starting with the 15,16 unsaturated estron derivative Xc as educt. The 3 hydroxy-derivative can be obtained by hydrolysis of the XXXI-6c compound. 30 WO 2006/125800 PCT/EP2006/062587 107 1ild. Optionally 2-substituted compounds of formula IV with substitution of the C17 keto function 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propanoic acid (IVp-2a-D1 F2) F F H IV-2a-D1F2 HO O HO The individual steps in the synthesis of the acid building block of the formula IVp-2a-D1F2 5 are depicted in the following scheme 12. SCHEME 12 O O F F H H H | H H H HO IVp-2c HO-2c 2cO VIIp-2c-D1F2 0 F F F F H H H H H H HO O HO O VIIp-2a-D1F2-1 O IVp-2a-D1F2 HO 3-(3-Benzyloxy-17-oxo-estra-1,3,5(10)-trien-15 -yl)-propanoic acid of formula IVp-2c is 10 transformed in the corresponding methyl ester by an esterification reaction as depicted in general flow diagram 11 using an EDCI coupling. Fluorination of the obtained methyl ester with deoxofluor gave compound Vllp-2c-D1 F2. Subsequent debenzylation, followed by saponification with LiOH afforded the desired building block IVp-2a-D1 F2. 15 Detailed Synthesis 3-(3-Benzyloxy-1 7-oxo-estra-13,5(1 0)-trien-1 513-yl)-propionic acid methyl ester (VI 13-2c) A mixture of compound IVb-2c (38 mmol), Et 3 N (117 mmol), MeOH (44 mmol), HOBt (44 mmol) and EDCI (49 mmol) in DCM (650 ml) was stirred overnight. The reaction mixture was washed with 1 N HCI and H 2 0. The organic layer was dried over Na 2

SO

4 and concentrated in vacuo to yield 20 Vllp-2c (38 mmol, 99%) as orange oil. 3-(3-Benzyloxy-1 7,17-difluoro-estra-1,3,5(1 0)-trien-1 513-yl)-propionic acid methyl ester Deoxofluor (50% in toluene, 247 ml, 670 mmol) was added to a solution of Vllp-2c (27.2 g, 60.9 mmol) in toluene (130 ml). The mixture was stirred for 5 d, during which two times 10 drops of WO 2006/125800 PCT/EP2006/062587 108 EtOH were added. DCM (200 ml) was added and the mixture was cooled on ice. Saturated Na

HCO

3 (300 mL) was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated in vacuo to give crude Vllp-2c-D1F2 (26.5 g). Purification by column chromatography (Si0 2 , DCM 5 heptan 2:1 to DCM) gave Vllp-2c-D1F2 (2.94 g, 6.3 mmol, 10%) as yellow oil. 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(10)-trien-15p-vl)-propionic acid methyl ester A mixture of Vllp-2c-DIF2 (2.94 g, 6.3 mmol), Pd/C (10%, 440 mg), MeOH (75 mL) and EtOAc (32 mL) was stirred for 2 d under 1 bar H 2 . After 1 day another portion of Pd/C (484 mg) was added. 10 The mixture was filtered over Celite and the filter cake was washed with MeOH and EtOAc. The fil trate was concentrated in vacuo to give 2.1 g of crude Vl1p-2a-D1 F2. Purification by column chro matography (Si0 2 , DCM) gave Vllp-2a-DI F2 (1.46 g, 3.9 mmol, 61%) as yellow oil. 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 513-yl)-propionic acid (IVp-2a-D1 F2) 15 A solution of LiOH*H 2 0 (934 mg, 22 mmol) in water (60 mL) was added to a solution of Vllp-2a DIF2 (1.46 g, 3.9 mmol) in THF (60 mL). The mixture was stirred overnight and concentrated in vacuo. Water (250 ml) was added and the mixture was washed with DCM and the pH was adjusted to 1. The aq. layer was extracted with DCM. The combined organic layers were dried over Na 2

SO

4 and concentrated in vacuo to yield IVp-2a-D1 F2 (1.2 g, 3.3 mmol, 85%) as yellow foam. 20 'H-NMR-listing: 1.027-1.34 (s, 3H), 1.408-2.421 (m, 15H), 2.837-2.960 (m, 2H), 6.573-6.651 (m, 2H), 7.121-7.257 (d, 1H). 1 9 F-NMR-listing: -104- -106 (d, 1F), -115 - -117 (d, 1F). 25 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-butanoic acid (lVa-3a-D1 F2) F F H IVa-3a-D1F2 HO OH HO' 0 The acid building block of formula lVa-3a-D1 F2 was synthesized starting from intermediate compound Xc and using the reaction steps as depicted in SCHEME 8B: The allyl group was intro duced into the 15, 16-unsaturated Estrone derivative of formula Xc by reaction with allylmagnesium 30 chloride, followed by an oxy-cope rearrangement catalysed by KH and 18-Crown-6. Subsequently, the resulting compound XXX-2c was reacted with acrylic acid methyl ester using a Grubb 11 catalyst (olefin metathesis). Then, deviating from SCHEME 8B, the 17-keto function of the resulting 4-(3 Benzyloxy-17-oxo-estra-1,3,5(10)-trien-15a-yl) but-2-enoic acid methyl ester was converted to a bisfluoro group using deoxofluor as described for Vllp-2c-D1 F2. Subsequently, the well known hy- WO 2006/125800 PCT/EP2006/062587 109 drogenation step was performed to obtain the butanoic acid ester side chain, and finally the ester was hydrolysed with LiOH to give the target compound. 'H-NMR-listing: 0.94 (s, 3H), 1.10-2.06 (m, 4H), 2.18-2.55 (m, 14H), 2.74-2.92 (m, 2H), 6.52 5 (d, 1H), 6.64 (dd, 1H), 7.15 (d, 1H) 1 9 F-NMR-listing: -104.5 (dd, 1F), -117.0 (d, 1F). 4-(3-Benzyloxy-1 7-difluoromethylene-estra-1,3,5(1 0)-trien-1 5-yl)-butan-1 -ol 4-(17-Difluoromethylene-3-hydroxy-estra-1,3,5(10)-trien-15-yl)-butyryl bromide F F F F H H 0 HO 10 XXXI1-4c-D-(I)-(a)=CF 2 OH Vp-3a-D-(I)-(a)=CF 2 Br Synthesis of XXXIp-4c-D-(I)-(a)=CF 2 was achieved in a 3-step reaction starting from inter mediate compound XXXIp-4c using the Horner reaction as described for general synthesis step D (1)-(a). Subsequently, the fluorinated alcohol derivative XXXI-4c-D-(1)-(a)=CF 2 was converted into the free acid by a Jones oxidation, followed by a debenzylation step using BBr 3 to deliver the de 15 sired intermediate Vp-3a-D-(1)-(a)=CF 2 . Detailed Synthesis: 3-Benzyloxy-1 5-[4-(tert-butvldimethylsilanyloxy)-butyll-estra-1,3,5(1 0)-trien-1 7-one To a solution of intermediate XXXIp-4c (108 mg; 0.25 mmol) and imidazole (41.0 mg; 0.60 20 mmol) in DMF (1 ml) tert-Butyldimethylsilylchloride (0.30 ml; 0.30 mmol; 1M in THF) was added dropwise. After stirring for 16 h at RT, the reaction mixture was poured into H 2 0 and extracted with DCM. The organic phases were dried over MgSO 4 . After removal of the solvent, the oily residue was purified by column chromatography (Si0 2 , DCM) to yield 3-Benzyloxy-15-[4-(tert butyldimethylsilanyloxy)-butyl]-estra-1,3,5(10)-tren-17-one (126 mg, 92%) as colourless oil. 25 [4-(3-Benzyloxy-1 7-difluoromethylene-estra-1,3,5(1 0)-trien-1 5-yl)-butoxyl-tert-butyldimethylsilane Lithium diisopropylamide (0.60 ml; 1.08 mmol; 1.8 M in THF/Heptane/Ethylbenzene) is added dropwise to a solution of Difluoromethyl-phosphonic acid diethylester (204 mg; 1.08 mmol) in THF (3 ml) at -78*C and stirred for 30 min. Subsequently, a solution of the ketone obtained in the 30 previous reaction step (148 mg; 0.27 mmol) in THF (4 ml) is added and the mixture is stirred for 30 min and further until the mixture was warmed to RT. The mixture is heated for 5 h under reflux and allowed to cool to RT. After addition of water, the solution is extracted with DCM. The combined or ganic phases are dried over MgSO 4 . After removal of the solvent, the residue is purified by column WO 2006/125800 PCT/EP2006/062587 110 chromatography (Si0 2 , DCM/Hexane 1:2) to yield [4-(3-Benzyloxy-17-difluoromethylene-estra 1,3,5(10)-trien-15-yl)-butoxy]-tert-butyldimethylsilane (107 mg, 68 %) as colorless oil. 4-(3-Benzvloxy-17-difluoromethylene-estra-1,3,5(10)-trien-15-vl)-butan-1-ol XXXlp-4c-D-(l)-(a)=CF9 5 A solution of the obtained TBDMS-Ether (97.0 mg; 167 pmol) in TBAF (1 ml; 1 mmol; 1 M in THF) was stirred for 4 h at RT. The reaction mixture is poured into H 2 0 and extracted with DCM. The combined organic phases are dried over MgSO 4 . After removal of the solvent, the residue is purified by column chromatography (Si0 2 , DCM) to yield XXXIp-4c-D-(1)-(a)=CF 2 (76.0 mg, 98 %) as yellow solid. 10 4-(3-Benzvloxy-17-difluoromethylene-estra-1,3,5(10)-trien-15-yl)-butyric acid IVp-3c-D-(l)-(a)=CF 2 After dissolving the alcohol XXXIp-4c-D-(1)-(a)=CF 2 in 10 ml acetone, Jones reagent (1g Cr0 3 , 7 ml H 2 0, 3 ml 100% H 2

SO

4 ) was added at 0*C up to the point the solution remained red dish. After stirring for 10 min, any excess of Jones reagent was destroyed by adding isopropanol. 15 After filtration over silicagel, the filtrate was evaporated to dryness. The residue was diluted with DCM and washed several times with water, dried over Na 2

SO

4 and again evaporated to dryness. The crude product was used further without any purification. 4-(17-Difluoromethylene-3-hydroxy-estra-1,3,5(10)-trien-15-yl)-butyryl bromide Vp-3a-D-(l)-(a)=CF9 20 The crude benzylated estrone acid derivative IVp-3c-D-(1)-(a)=CF 2 was dissolved in 10 ml dry DCM and few drops BBr 3 were added at ambient temperature. The reaction mixture was stirred for 1 h and directly used in further reaction steps without any work-up. 25 4-(3-Benzvloxy-1 7-trifluoromethyl-estra-1,3,5(10),16-tetraen-1 5-vl)-butan-1 -ol 4-(3-Hydroxy-17-trifluoromethyl-estra-1,3,5(10),16-tetraen-15-vl)- butyryl bromide CF,

CF

3 HH H H H H HO XXXIp-4c-D-(I)-(d)=CF3 OH VP-3a-D-(I)-(d)=CF3 Br Synthesis of XXXlp-4c-D-(l)-(d)-CF 3 was achieved in a 4-step reaction starting from interme diate compound XXXIp-4c as described for general synthesis step D-(1)-(d). Subsequently, the 30 fluorinated alcohol derivative XXXI-4c-D-(1)-(d)=CF 3 was converted into the free acid by a Jones oxidation, followed by a debenzylation step using BBr 3 to deliver the desired intermediate Vp-3a-D (I)-(d)-CF 3

.

WO 2006/125800 PCT/EP2006/062587 111 3-Benzyloxy-1 5-(4-hydroxybutyl)-1 7-trifluoromethyl-estra-13,5(1 0)-trien-1 7-ol (Trifluoromethyl)trimethylsilan (7.60 ml; 15.0 mmol; 2M in THF) was added to a solution of in termediate XXXIp-4c (1.08 g; 2.50 mmol) in THF precooled to 0 0 C. After addition of TBAF (60.0 mg; 0.63 mmol), the reaction mixture was stirred for 0.5 h at 0 0 C and for 16 h at RT. Water was 5 added and the resulting the solution was extracted with ether. The combined organic phases were dried over MgSO 4 . After removal of the solvent, the residue was dissolved in TBAF solution (10.0 ml; 10.0 mmol; 1 M in THF) and the resulting mixture was stirred for 4 h at RT. Water was added and the resulting the solution was extracted with ether. The combined organic phases were dried over MgSO 4 . The remaining oil was purified by column chromatography (SiO 2 ; Ether/DCM 1:1) 10 yielding the title compound (942 mg, 75%) as colourless oil. 2,2-Dimethylpropionic acid 4-(3-benzvloxy-17-hydroxy-17-trifluoromethyl-estra-1,3,5(10) trien-1 5-vl)-butylester Pivaloylchloride (0.50 ml; 4.10 mmol) was added dropwise to a solution of 3-Benzyloxy-15 15 (4-hydroxybutyl)-17-trifluoromethyl-estra-1,3,5(10)-trien-17-ol (1.65 g; 3.28 mmol) in pyridine (15 ml) at 0*C. After stirring for 2 h, the reaction mixture was poured into ice water and stirred for an other h. After extraction with DCM, the combined organic phases were dried over MgSO 4 . After evaporation of the solvent, the residue was purified by column chromatography (SiO 2 , DCM) yield ing the title compound (1.85 g, 96%) as colourless oil. 20 2,2-Dimethylpropionic acid 4-(3-benzvloxy-17-trifluoromethyl-estra-1,3,5(10),16-tetraen-15 yl)-butylester Phosphorylchloride (0.25 ml; 200 pmol) was added to a solution of 2,2-Dimethylpropionic acid 4-(3-benzyloxy-17-hydroxy-17-trifluoromethyl-estra-1,3,5(10)-trien-15-yl)-butylester (80.0 mg; 25 136 pmol) in pyridine (2.50 ml) and the resulting mixture is heated under reflux for 24h. The mixture was allowed to cool to RT, diluted with ice water and extracted with ether. The combined organic phases were dried over MgSO 4 and the solvent was evaporated. The residue was purified by col umn chromatography (SiO 2 , DCM) yielding the title compound (60.0 mg, 78%) as colourless oil. 30 4-(3-Benzvloxy-17-trifluoromethyl-estra-1,3,5(10),16-tetraen-15-vl)-butan-1-ol XXXIp-4c-D-(l)-d-CF 3 DIBAH (1.00 ml; 1.00 mmol; 1 M in THF) was added dorpwise to a solution of the pivaloate (60.0 mg; 106 pmol) in DCM (5 ml) at -78*C. After stirring for 6h, 1 N HCI (20 ml) was added and the reaction mixture was extracted with DCM. The combined organic phases were dried over MgSO 4 and the solvent was evaporated. The residue was purified by column chromatography 35 (SiO 2 , DCM) yielding XXXlp-4c-D-(l)-d-CF 3 (46.0 mg, 90) as colourless oil. 4-(3-Benzvloxy-17-trifluoromethyl-estra-1,3,5(10),16-tetraen-15-vl)-butyric acid IVp-3c-D-(l)-(d)-CF 3 WO 2006/125800 PCT/EP2006/062587 112 After dissolving 180 mg of the alcohol XXXIp-4c-D-(1)-(d)-CF 3 in 10 ml acetone, Jones re agent (1g Cr0 3 , 7 ml H 2 0, 3 ml 100% H 2

SO

4 ) was added at 0*C up to the point the solution re mained reddish. After stirring for 10 min, any excess of Jones reagent was destroyed by adding isopropanol. After filtration over silicagel, the filtrate was evaporated to dryness. The residue was 5 diluted with DCM and washed several times with water, dried over Na 2

SO

4 and again evaporated to dryness. The crude product was used further without any purification. 4-(3-Hydroxy-17-trifluoromethyl-estra-1,3,5(10)-trien-15-yl)-butyryl bromide Vp-3a-D-(1)-(d)-CF 3 The crude benzylated estrone acid derivative IVp-3c-D-(1)-(d)-CF 3 was dissolved in 10 ml dry 10 DCM and few drops BBr3 were added at ambient temperature. The reaction mixture was stirred for 1 h and directly used in further reaction steps without any work-up. Ille. Optionally 2-substituted compounds of formula XV (Protected amine building block) (n 1 - 6) 0 0 R14 H (XV) H H ()n=l-6 PG ONH 2 15 Protected amine building block XV-1 (n = 1): The individual steps in the synthesis of amine building block of the formula XV-1 are de picted in the following scheme 13. 20 SCHEME 13 01NH 2 O 0 0 0 R14H 2. NaBH 4 H. H PG H H O PG O NH 0 H (XIII-O) (XIV-1) 0 0 0 R14 H

HCI/H

2 0 R14 H Pd/C, H2 PG O NH 2 PG, NH 3 CI (XV-1) (XXIX-1) Dissolving aldehydes XIII-Ob (PG=CH 3 ) or XIll-0c (PG=benzyl) in benzylamine and reduction of the residual imine in THF gave benzylamine XIV-1b (PG=CH 3 ) and XIV-1c (PG=benzyl), which were debenzylated to XV-1b (PG=CH 3 ) and XV-1a (PG=H), using Pd/C and H 2 at 5 bar, and dis- WO 2006/125800 PCT/EP2006/062587 113 solved in dilute HCI to give the respective ammonium chlorides XXIX-lb (PG=CH 3 ) and XXIX-1a (PG=H). Standard purification methods failed due to what seems to be instability of these ammo nium salts. For these amines it was known that these should be treated as HCI salts since the free amine is not stable (ene-amines), but even the salts seem to be at least heat-sensitive. The crude 5 reaction mixture has a purity of -90% (HPLC-MS). Amine building block XVa-3: (n = 3): The individual steps in the synthesis of amine building block of the formula XVa-3 are de picted in the following scheme 16. 10 SCHEME 16: 0 H!N H! H R14 O Br(Ph) 3 P N PPh 3 R14 H O PG RI 01 0 H (XIIIa-0) (XXXVII-3) NH 2 O O 0 Pd/C, H 2 R 1 4 H HCI/H 2 0 R14 PGH PG, (XVa-3) NH 2 (XXIXa-3) NH 3 CI The protected aldehyde derivative of formula (XIllx-0) is converted into the corresponding aminopropenyl by a Wittig reaction (see also SCHEME 4). The aminopropenyl (XXXVII-3) is sub 15 sequently reduced to the 15-aminopropyl derivative of formula XVa-3. The protecting ketal group is converted into the 17-oxo group via acid hydrolysis. The same kind of procedure can be applied using different Wittig reagents of the general formula Hal(Ph) 3

P-(CH

2 )n=3-5-R* in order to obtain amine building blocks with longer side chains (i.e. 20 n = 4, 5, or 6), wherein R* for example represents -N=P(Ph) 3 , -N 3 , or -NH-CO-0-CH 3 . Amine building block XVa-4: (n = 4): 0 0 (XVa-4) R14 H H H H PG0

NH

2 WO 2006/125800 PCT/EP2006/062587 114 Furthermore, the amine building block XVa-4b was synthesized corresponding to SCHEME 16 using HalPh 3

P-CH

2

-CH

2

-CH

2

-N

3 as Wittig reagent. (LC-MS (ES+): rt 4.57 min, m/z (rel. Intens) 386 [(M+H)+, 100%]) 5 Amine building block XVp-4: (n = 4): The individual steps in the synthesis of amine building block of the formula XVp-4 with P con figuration at the C1 5 atom of the steroidal core are depicted in the following scheme 17. SCHEME 17 O HO OH O R,4 H H pTosOH R 1 4 PGIOH OH PGH OH PGG; (XXXI13-4) (XXXIIp-4)

O-.NH

2 R14 H 2. NaBH 4 R14 H Pd/C, H 2 A H H H PG PGO H HN (XIIIP-3) (XIVP-4) PGO / PGO (XVP-4) NH2 (XXIX-4) NHc 10 In a first step, the 17 oxo function of the butanol derivative of the formula XXXIp-4 (for syn thesis of XXXIp-4 see above) is converted into the ketal group (compound of formula XXXIlp-4). Then, the alcohol function is selectively reduced to the aldehyde giving compound of the formula XIllp-3. The protected aldehyde derivative of the formula XIllp-3 is converted into a secondary 15 amine by addition of Benzylamine and subsequent reduction (reductive amination). Further reduc tion of the secondary amine delivers the desired, still protected amine building block of the formula XVp-4. The protecting ketal group can be converted into the 17-oxo group via acid hydrolysis. The same kind of procedure can be applied for n = 5 or 6 and for other substituents within 20 the R 1 position.

WO 2006/125800 PCT/EP2006/062587 115 Amine building block (n = 1 - 6) of general formula XXIX 0 H R14(XXIX) H H PG ')= O NH 2 *HCI Alternatively, the synthesis of the amine building blocks of general formula XXIX can also be performed starting with an activated alcohol function and a subsequence substitution reaction, and 5 does not need any protection of the Estron-C17 keto function according to the following general scheme 18. SCHEME 18 0 0 OH

R

14 H

R

1 4 H PG11 H( )n 1-6 PG 1 O Hn H H O OH (XLII) O SO-CH 3 0

R

14 H R 14 H H HH H PG s ( n=1-6 PG O 0 N 3

NH

2 *HCI (XLIII) (XXIX) 10 Step C - Synthesis of Intermediates of general formula C-(I) with R 14 = H 0 R14 .H C-(l) PG, )n OA ''R 2 The synthesis of the intermediates falling under the general formula C-(1), wherein R repre sents H, is fully disclosed in international patent application WO 2005/047303, and was performed 15 according to the reaction schemes depicted in general flow diagrams I to XV herewithin. The fol lowing table gives an overview of exemplary intermediates prepared. The number given in the first column corresponds to the compound number as disclosed in international patent application WO 2005/047303.

WO 2006/125800 PCT/EP2006/062587 116 Table 1: Exemplary intermediates of the general formula VI (amide derivatives) 0 C-(VI) PGA A, H H n H/R4 PGs C15 PG or 2 4 S HPLC No. n stereo RI - -N R9 m/z 1 3 beta -H morpholin-4-yl 2 3 beta -CH 3 morpholin-4-yl 4B 3 beta -CH 3 methyl H 4C 3 beta benzyl methyl H 5 3 beta -CH 3 Cyclopropyl H 409.3 5.89 7 3 beta -CH 3 Furan-2-yl H 449.3 5.74 9 3 beta -CH 3 2-Morpholin-4-yl-ethyl H 482.2 5.05 12 3 beta -CH 3 1-Benzyl-piperidin-4-yi H 542.3 5.24 13 3 beta -CH 3 Quinolin-3-yl H 496.3 5.98 15 3 beta -CH 3 3,4-Dichloro-benzyl H 527.2 6.35 16 3 beta -CH 3 3,4-Dimethoxy-benzyl H 519.3 5.66 17 3 beta -CH 3 2-Hydroxy-2-phenyl-ethyl H 489.3 5.60 18 3 beta -CH 3 2-Dimethylamino-ethyl H 440.3 4.71 19 3 beta -CH 3 2-(2-Hydroxy-ethoxy)-ethyl H 457.3 5.04 21 3 beta -CH 3 2-(3,4-Dimethoxy-phenyl)- H 533.3 5.79 ethyl 23 3 beta -CH 3 3-Imidazol-1-yi-propyl H 477.3 4.95 24 3 beta -CH 3 1H-Benzoimidazol-2-yi-methyl H 499.3 5.39 25 3 beta -CH 3 4-Hydroxy-3-methoxy-benzyl H 505.3 5.49 26 3 beta -CH 3 Carbamoyl-methyl H 426.2 6.30 28 3 beta -CH 3 2-(4-Sulfamoyl-phenyl)-ethyl H 552.3 5.37 30 3 beta -CH 3 4-Trifluoromethoxy-benzyl H 543.3 6.35 32 3 beta -CH 3 4-Fluoro-3-trifluoromethyl- H 545.3 6.30 benzyl 33 3 beta -CH 3 2-Oxo-tetrahydro-furan-3-yl H 453.3 5.32 34 3 beta -CH 3 2-Oxo-azepan-3-yl H 480.3 5.33 35 3 beta -CH 3 4-Hydroxy-cyclohexyl H 467.3 5.18 36 3 beta H 2-(7-Methyl-1H-indol-3-yl)- H ethyl 37 3 beta H 2,4-Difluoro-benzyl H 38 3 beta H Benzyl methyl 39 3 alpha H Benzyl H 40 3 alpha H Morpholin-4-yl 42 0 alpha -CH 3 2-(1H-Indol-3-yl)-ethyl H 470.3 1.92 44 0 alpha -CH 3 1-Benzyl-pyrrolidin-3-yl H 486.3 1.48 47 0 alpha -CH 3 Phenethyl H 431.2 1.95 49 0 alpha -CH 3 Cyclopropylmethyl H 381.2 1.83 .50 01 alpha -CH 3 Cyclohexylmethyl H 423.3 2.06 WO 2006/125800 PCT/EP2006/062587 117 C15 PG or S2 4 HPLC No. n stereo R 1 -N R m/z 51 0 alpha -CH 3 2,2-biphenyl-ethyl H 507.3 2.12 54 0 alpha -CH 3 3,3-biphenyl-propyl H 521.3 2.14 56 0 alpha -CH 3 2-Pyridin-2-yl-ethyl H 432.2 1.46 60 0 alpha -CH 3 4-Methoxy-benzyl H 447.2 1.89 63 0 alpha -CH 3 sec-butyl H 383.2 1.87 66 0 alpha -CH 3 Bicyclo[2.2.1]hept-2-yl H 421.3 2.02 71 0 alpha -CH 3 Indan-2-yl H 443.2 1.97 73 0 alpha -CH 3 2-Hydroxy-ethyl H 371.2 1.55 77 0 alpha -CH 3 3-Morpholin-4-yl-propyl H 454.3 1.37 79 0 alpha -CH 3 4-Phenyl-butyl H 459.3 2.08

-(CH

2

)

3 -CO-0-CH 3 / 80 0 alpha -CH 3 (butyric acid methyl ester)-4- H 427.2 1.74 yl 1-Oxo-1-benzoxy-propan-2-yl / 81 0 alpha -CH 3 (Propionic acid benzyl ester)- H 489.3 1.99 2-yl 83 0 alpha -CH 3 1,2,3,4-Tetrahydro- H 457.3 2.08 naphthalen-1-yl __________ 84 0 alpha -CH 3 2-Fluoro-benzyl H 435.2 1.92 85 0 alpha -CH 3 3-Hydroxy-propyl H 385.2 1.58 89 0 alpha -CH 3 2-Phenyl-propyl H 445.3 2.02 97 0 alpha -CH 3 Thiophen-2-yl-methyl H 423.2 1.91 103 0 alpha -CH 3 1-Hydroxymethyl-cyclopentyl H 425.3 1.81 105 0 alpha -CH 3 5-Methyl-thiazol-2-yl H 424.2 1.95 107 0 alpha -CH 3 4-Benzyl-piperdin-1-yl 485.3 2.22 109 0 alpha -CH 3 3,4-Dihydro-H-isoquinolin-2-yl 443.2 2.05 111 0 alpha -CH 3 4-Pyridin-2-yl-piperazin-1-yl 473.3 1.63 117 0 alpha -CH 3 4-(4-Chloro-benzyl)-piperazin-1-yl 520.2 1.67 118 0 alpha -CH 3 4-(3-Chloro-phenyl)-piperazin-1-yl 506.2 2.16 120 0 alpha -CH 3 4-[2-(2-Hydroxy-ethoxy)-ethyl-piperazin-1-y 484.3 1.39 121 0 alpha -CH 3 4-(4-Chloro-phenyl)-piperazin-1-yl 506.2 2.16 124 0 alpha -CH 3 1,3,4,9-Tetrahydro-beta-carbolin-2-yl 482.3 2.04 125 0 alpha -CH 3 4-Hydroxy-4-pheny-piperidin-1-yl 487.3 1.90 126 0 alpha -CH 3 4-(2-Chloro-phenyl)-piperazin-1-yl 506.2 2.20 127 0 alpha -CH 3 4-(4-Methoxy-phenyl)-piperazin-1-y 502.3 2.01 128 0 alpha -CH 3 1-Piperidine-3-carboxylic acid amide / 438.3 1.63 3-(carboxylic acid amide)-piperidin-1-yl 130 0 alpha -CH 3 4-Methyl-piperazin-1-yl 410.3 1.40 132 0 alpha -CH 3 2-Methoxymethyl-pyrrolidin-1-yl 425.3 1.93 133 0 alpha -CH 3 4-(2-Fluoro-phenyl)-piperazin-1-yl 490.3 2.10 138 0 alpha -CH 3 3,6-Dihydro-2H-pyridin-1-yl 393.2 1.92 140 0 alpha -CH 3 1-Pyrrolidine-2-carboxylic acid amide / 424.2 1.60 2-(carboxylic acid amide)-pyrrolidin-1-yl 145 0 alpha -CH 3 4-Pyrrolidin-1-yl-piperidin-1-yl 464.3 1.43 147 0 alpha -CH 3 Azetidin-1-yl 367.2 1.74 150 0 alpha -CH 3 Propyl cyclopropylmethyl 423.3 2.13 151 0 alpha -CH 3 2-Cyano-ethyl pyridin-3-ylmethyl 471.3 1.67 WO 2006/125800 PCT/EP2006/062587 118 C15 PG or S2 4 HPLC No. n stereo R

-

m/z 154 0 alpha -CH 3 Benzyl 2-dimethylamino-ethyl 488.3 1.56 156 0 alpha -CH 3 2-Methoxy-ethyl 2-Methoxy-ethyl 443.3 1.90 157 0 alpha -CH 3 Methyl 1-methyl-piperidin-4-yl 438.3 1.43 161 0 alpha -CH 3 Propyl propyl 411.3 2.11 162 0 alpha -CH 3 Methyl 2-dimethylamino-ethyl 412.3 1.42 163 0 alpha -CH 3 Methyl phenethyl 445.3 2.08 164 0 alpha -CH 3 Methyl allyl 381.2 1.92 165 0 alpha -CH 3 Ethyl pyridin-4-yl-methyl 446.3 1.61 166 0 alpha -CH 3 Methyl methyl 355.2 1.78 168 1 alpha -CH 3 biphenyl-methyl H 507.3 2.14 171 1 alpha -CH 3 Naphthalen-1-ylmethyl H 481.3 2.10 183 1 alpha -CH 3 2-Piperidin-1-yl-ethyl H 452.3 1.47 189 1 alpha -CH 3 Cyclopentyl H 409.3 1.95 191 1 alpha -CH 3 3-Phenyl-propyl H 459.3 2.05 195 1 alpha -CH 3 1-Ethyl-propyl H 411.3 1.99 197 1 alpha -CH 3 2-Methoxy-ethyl H 399.2 1.74 198 1 alpha -CH 3 2-Pyrrolidin-1-yl-ethyl H 438.3 1.46 199 1 alpha -CH 3 2-(5-Methoxy-1H-indol-3-yl)- H 514.3 1.91 ethyl 203 1 alpha -CH 3 1-Phenyl-ethyl H 445.3 2.02 204 1 alpha -CH 3 1,2-biphenyl-ethyl H 521.3 2.17 206 1 alpha -CH 3 2,6-Dimethoxy-benzyl H 491.3 2.00 207 1 alpha -CH 3 4-Fluoro-benzyl H 449.2 1.98 208 1 alpha -CH 3 3,5-Dimethoxy-benzyl H 491.3 1.95 209 1 alpha -CH 3 2-Phenoxy-ethyl H 461.3 1.99 211 1 alpha -CH 3 1-Naphthalen-1-yl-ethyl H 495.3 2.13 219 1 alpha -CH 3 2,4-bifluoro-benzyl H 467.2 2.00 222 1 alpha -CH 3 Isobutyl H 397.3 1.94 224 1 alpha -CH 3 2-Cyclohex-1-enyl-ethyl H 449.3 2.18 225 1 alpha -CH 3 2-Hydroxy-1-methyl-ethyl H 399.2 1.65 226 1 alpha -CH 3 2-Methylsulfanyl-ethyl H 415.2 1.85 227 1 alpha -CH 3 3,4,5-Trimethoxy-benzyl H 521.3 1.90 229 1 alpha -CH 3 2-Hydroxy-cyclohexyl H 439.3 1.76 233 1 alpha -CH 3 3-biethylamino-propyl H 454.3 1.49 234 1 alpha -CH 3 Hexyl H 425.3 2.11 235 1 alpha -CH 3 3,4-bifluoro-benzyl H 467.2 1.99 236 1 alpha -CH 3 2-Trifluoromethyl-benzyl H 499.2 2.05 (3-Methyl-butyric acid methyl 238 1 alpha -CH 3 ester)-2y / H 455.3 1.92 2-(3-methyl)-butyric acid methyl ester 239 1 alpha -CH 3 5-Methyl-thiazol-2-yl H 438.2 1.95 240 1 alpha -CH 3 Cyclobutyl H 395.2 1.85 241 1 alpha -CH 3 4-Benzyl-piperazin-1-yl 500.3 1.56 243 1 alpha -CH 3 4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-y 544.3 1.54 244 1 alpha -CH 3 4-(2-oxo-1,3-dihydro-benzoimidazol-1-y)-piperidin-1-y 541.3 1.83 246 1 alpha -CH 3 2,5-bihydro-pyrrol-1-yl 393.2 1.89 WO 2006/125800 PCT/EP2006/062587 119 C15 PG or 2 4 HPLC No. n stereo R

-

m/z stereo - N I--, R2 M/ [m n 247 1 alpha -CH 3 4-Phenyl-piperazin-1-yl 486.3 2.11 249 1 alpha -CH 3 Pyrrolidin-1-yl 395.2 1.89 250 1 alpha -CH 3 4-(4-Fluoro-phenyl)-piperazin-1-yl 504.3 2.10 251 1 alpha -CH 3 4-(2-Methoxy-phenyl)-piperazin-1-yl 516.3 2.08 252 1 alpha -CH 3 4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl 535.2 2.04 253 1 alpha -CH 3 4-(4-trifluoromethyl-phenyl)-piperazin-1-y 554.3 2.23 256 1 alpha -CH 3 4-Methyl-[1,4]diazepan-1-yl 438.3 1.43 259 1 alpha -CH 3 1,4-Dioxa-8-aza-spiro[4.5]decan-8-yl 467.3 1.89 260 1 alpha -CH 3 1-piperidine-4-carboxylic acid ethyl ester / 481.3 1.98 4-(carboxylic acid ethyl ester)-piperidin-1-yl 266 1 alpha -CH 3 Azepan-1-yl 423.3 2.08 268 1 alpha -CH 3 4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl 554.3 2.23 269 1 alpha -CH 3 3-Hydroxy-pyrrolidin-1-yl 411.2 1.62 271 1 alpha -CH 3 4-Oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decan-8-y 555.3 1.87 273 1 alpha -CH 3 4-pyridin-4-yl-piperazin-1-yl 487.3 1.46 274 1 alpha -CH 3 4-Hydroxy-piperidin-1-yl 425.3 1.64 275 1 alpha -CH 3 octahydro-quinolin-1-yl 463.3 2.29 276 1 alpha -CH 3 3-Hydroxy-piperidin-1-yl 425.3 1.70 279 1 alpha -CH 3 1-pyrrolidine-2-carboxylic acid methyl ester / 453.3 1.86 2-(carboxylic acid methyl ester)-pyrrolidin-1-yl 281 1 alpha -CH 3 2-Hydroxymethyl-pyrrolidin-1-yl 425.3 1.73 282 1 alpha -CH 3 4-o-tolyl-piperazin-1-yl 500.3 2.23 283 1 alpha -CH 3 4-(2-Ethoxy-phenyl)-piperazin-1-yl 530.3 2.14 284 1 alpha -CH 3 4-Cyclohexyl-piperazin-1-yl 492.3 1.48 286 1 alpha -CH 3 thiazolidin-3-yl 413.2 1.89 288 1 alpha -CH 3 methyl 2-pyridin-2-yl-ethyl 460.3 1.66 289 1 alpha -CH 3 Methyl 2,3,4,5,6- 519.3 1.49 pentahydroxy-hexyl 293 1 alpha -CH 3 methyl naphthalen-1-ylmethyl 495.3 2.20 296 1 alpha -CH 3 benzyl ethyl 459.3 2.15 297 1 alpha -CH 3 benzyl phenethyl 535.3 2.31 299 1 alpha -CH 3 methyl Butyl 411.3 2.06 302 1 alpha -CH 3 Benzyl 2-cyano-ethyl 484.3 2.01 303 1 alpha -CH 3 propyl methyl 397.3 1.97 306 1 alpha -CH 3 phenethyl methyl 459.3 2.08 308 1 alpha -CH 3 ethyl pyridin-4-ylmethyl 460.3 1.61 312 2 beta -CH 3 Furan-2-ylmethyl H 435.24 5.93 313 2 beta -CH 3 Methyl Cyclohexyl 451.31 6.86 316 2 beta -CH 3 morpholin-4-yl 425.57 318 2 beta -CH 3 pyridin-3-ylmethyl H 446.26 5.33 320 2 beta -CH 3 benzyl H 323 2 beta -CH 3 4-Chloro-benzyl H 479.22 6.45 326 2 beta -CH 3 Butyl H 411.28 6.1 329 2 beta -CH 3 5-methyl-thiazol-2-yl H 452.21 6.26 329A 2 beta -H 5-methyl-thiazol-2-yl H 452.21 6.26 332 4 beta -CH 3 Cyclooctyl H 493.36 5.05 334 4 beta -CH 3 2-thiazol-4-yl-acetic acid H 552.27 4.6 WO 2006/125800 PCT/EP2006/062587 120 C15 PG or 2 4 HPLC No. n stereo R 1 -N R m/z ethyl ester / 4-(acetic acid ethyl ester) thiazol-2-yl 335 4 beta -CH 3 Benzo[1,3]dioxol-5-ylmethyl H 517.28 4.41 336 4 beta -CH 3 morpholin-4-yl 453.29 4.2 339 4 beta -CH 3 pyridin-4-ylmethyl H 474.29 3.93 341 4 beta -CH 3 2-Methoxy-benzyl H 503.3 4.56 342 4 beta -CH 3 3-Fluoro-benzyl H 491.28 4.54 347 4 beta -CH3 2-(7-methyl-1H-indol-3-yl)- H 540.34 4.58 ethyl 348 5 beta -CH 3 Cyclohexyl H 479.34 7 354 5 beta -CH 3 morpholin-4-yl 467.65 355 5 beta -CH 3 thiomorpholin-4-yl 483.28 6.86 358 5 beta -CH 3 Phenyl H 473.29 7.00 363A 5 beta -H 2-(4-Hydroxy-phenyl)-ethyl H 364 5 beta -CH 3 Methyl benzyl 501.32 7.25 366 5 beta -CH 3 2-Thiophen-2-yi-ethyl H 507.28 6.81 368 5 beta -CH 3 5-methyl-thiazol-2-yl H 494.26 6.87 Table 2: Intermediates of the general formula VIl (ester derivatives) O H C-(VIl) O-R2 PG1 1 n O0 C15 Pp2 HPLC Rt INo. n 1 PG or I2 MS m/Z HPCt Stereo R [min] 369 5 beta -CH 3 isopropyl 5 Table 3: Intermediates of the general formula Vill (ketone derivatives) O H R2 C-(Vll) PG H n No. n stereo oR M2Sm/z | C15 G or S HPL e -m/Z [mCH]3 370 2 beta -CH 3 ethyl WO 2006/125800 PCT/EP2006/062587 121 Table 4: Intermediates of the general formula XLI (Hydrazide derivatives) 0 H H H 2 PG H{ H N-N C-(XLI) PGH/

R

4 0 C5R2 p4 HPL C15 P& or HPL No. n ste- , R4 Ct reo -N R m/z [mi 371 2 beta -CH 3 morpholin-4- y 440.27 3.62 372 2 beta -CH 3 7-chloro-quinolin-4-yl H 531.23 3.9 374 2 beta -CH 3

-CO-CH

3 / acetyl H 412.24 3.43 376 2 beta -CH 3

-CH

2 -CO-0-CH 2

-CH

3 H 456.26 3.82 377 2 beta -CH 3 2-Fluoro-phenyl H 464.25 4.21 381 3 beta -CH 3 Azepan-1-yl 466.32 4.45 382 3 beta -CH 3 2-(1H-indol-3-yl)-acetyl H 541.29 3.93 386 3 beta -CH 3 -CO-phenyl H 488.27 3.93 388 3 beta -CH 3 methyl phenyl 474.29 4.37 390 3 beta -CH 3 3,5-dichloro-phenyl H 528.19 4.66 391 3 beta -CH 3 -CO-(3,4,5-trimethoxy)-phenyl H 578.3 3.92 393 3 beta -CH 3 3-methoxy-phenyl H 490.28 4.19 394 3 beta -CH 3 6-chloro-pyridazin-3-yi H 496.22 4.47 395 3 beta -CH 3 2-Methoxymethyl-pyrrolidin-1-yl 482.31 4.03 401 4 beta -CH 3 methyl Methyl 426.29 3.94 405 4 beta -CH 3 benzothiazol-2-yl H 531.26 5.19 406 4 beta -CH 3 4-methyl-piperazin-1-yl 481.33 3.46 408 5 beta -CH 3 piperidin-1- y 480.34 4.58 409 5 beta -CH 3 4-methanesulfonyl-phenyl H 566.28 4.15 410 5 beta -CH 3 -CO-(3-Methoxy-)phenyl H 546.31 4.26 411 5 beta -CH 3 acetyl H 454.28 3.8 413 5 beta -CH 3 benzyl H 502.32 4.78 416 5 beta -CH 3 3,4-dichloro-phenyl H 556.23 4.9 5 Table 5: Intermediates of the general formula XVII (Urea derivatives) 0 H C-(XVI l) H H R 2 PGs " I OAN N'H/R4

O

WO 2006/125800 PCT/EP2006/062587 122 PG 4HPLC C15 P MS RtL stereo or R 4 m/z [] R-N [min] R2 420 1 alpha -H 3-nitro-phenyl -H 436.22 3.74 421 1 alpha -H 3,4-Dichloro-benzyl -H 486.21 3.98 423 1 alpha -H Benzyl -H 490.25 3.8 427 1 alpha -H 4-methoxy-phenyl -H 463.21 3.76 428 1 alpha -H 3-Cyano-phenyl -H 432.24 3.56 433 1 alpha -H isopropyl -H 454.32 4.17 434 1 alpha -H octyl -H 442.25 3.34 443 3 beta -CH 3 3-Methoxy-phenyl -H 490.28 4.33 444 3 beta -CH 3 3-trifluoromethyl-phenyl -H 528.26 4.69 445 3 beta -CH 3 4-Fluoro-phenyl -H 478.26 4.36 448 3 beta -CH 3 4-trifluoromethyl-phenyl -H 528.26 4.7 451 3 beta -CH 3 naphthalen-1-yl -H 510.29 4.5 453 3 beta -CH3 2-benzoic acid methyl ester / -H 518.28 4.76 2-(carboxylic acid methyl ester)-phenyl 455 3 beta -CH 3 3-Acetyl-phenyl -H 502.28 4.23 458 3 beta -CH 3 Biphenyl-2-yl -H 536.3 4.79 462 3 beta -CH 3 4-(6-methyl-benzothiazol-2-y)-phenyl -H 466 4 beta -CH 3 2,4-Dichloro-phenyl -H 542.21 5.19 467 4 beta -CH 3 3-Fluoro-phenyl -H 492.28 4.63 475 4 beta -CH 3 Cyclohexyl -H 480.34 4.56 481 4 beta -CH 3 4-Acetyl-phenyl -H 516.3 4.37 482 4 beta -CH 3 4-trifluoromethoxy-phenyl -H 558.27 4.89 485 4 beta -CH 3 naphthalen-2-yl -H 524.3 4.82 486 4 beta -CH 3 3-propionic acid ethyl ester / -H 498.31 4.18 1 1_ 1-ethoxy-1-oxo-propan-3-yl 488 4 beta -CH 3 3,4-Dimethoxy-phenyl -H 534.31 4.28 489 4 beta -CH 3 Benzo[1,3]dioxol-5-yl -H 518.28 4.42 490 4 alpha -H 4-benzoic acid ethyl ester / -H 532 5.91 4-(carboxylic acid ethyl ester)-phenyl 491 4 alpha -H Cyclohexylmethyl -H 480 6.42 492 4 alpha -H Phenyl -H 460 5.65 Table 6: Intermediates of the general formula XIX (sulfamide derivatives) O H C-(XIX) H H R2 PG " O | ON H/R4 II 0 5 WO 2006/125800 PCT/EP2006/062587 123 C15 P6 or 24 No. n stereo R1 -N R 4 493 ~~~ ~ ~ I- 2 lh -H -pey-el 494 2 alpha _-CH 3 2-phaen-yl-ethyl -H 495 2 alpha -CH 3 3,3-biphenyl-propyl -H 496 2 alpha -CH 3 3-Methyl-butyl -H 497 12 alpha -CH 3 2-((Phenylsulfonyl)methyl)-benzy -H 498 2 alpha -CH 3 Naphthalen-2-yi-methyl -H 499 2 alpha -CH 3 2-(Ebif luoromethoxy)benzyl -H 500 2 alpha -CH 3 2 -[N,N-(2 -Hydroxy-ethyl)-phenyl-amino ]-ethyl -H 501 2 alpha -CH 3 2,5-Bis(trif luoromethyl)-benzyl -H 502 2 alpha -CH 3 acetic acid 2-ethyl ester /-H I__ I__ -CH 2

-CH

3

-O-CO-CH

3 503 2 alpha -CH 3 Naphthalen-1-yi-carbamic acid 2-ethyl ester -H 504 2 alpha -CH 3 2,3-Ebichlorophenyl-carbamic acid 2-ethyl ester -H 505 2 alpha -CH 3 2,3-bihydro-benzo[1,4]dioxin-2-ylmethyI -H 506 2 alpha -CH 3 4-Fluoro-2,3-dihydro-benzof uran-2-yi-methyl -H 507 2 alpha -CH 3 I2-Phenyl-benzyl -H 508 2 alpha -CH 3 2-Indol-3-yi-ethyl -H 2 alpha -CH 3

-CH

2 -(3-benzoic acid methyl ester) /-H 509 _________ (3-carboxylic acid methyl ester)-benzyl 511 2 alpha -CH 3 3,5-Bis(trif luoromethyl)benzyl -H 512 2 alpha -CH 3 I3-Benzoyl-benzyl -H 513 2 alpha_ -CH 3 3,2-bihydroxy-propyl -H 514 2 alpha -CH 3 2-(4-Chlorobenzoyl)-benzof uran-3-yi-methyl -H 2 alpha -CH 3 3-propionic acid ethyl ester /-H 515 _ ___ __ 1-ethoxy-l-oxo-propan-3-yi 516 2 alpha -CH 3 I3-Phenoxy-propyl -H 517 2 alpha_ -CH 3 2-(4-Acetophenone)-ethyl -H 518 2 alpha -CH 3 1,2,3-Thiadiazol-4-yi-benzyl -H 2 alpha -CH 3

-CH

2 -(4-benzoic acid methyl ester) /-H 519 _________ (4-carboxylic acid methyl ester)-benzyl 2 alpha -CH 3

-CH

2 -(4-phenyl-acetic acid phenacyl ester) /-H 520 _________ -CH 2 -(4-phenyl-CH 2

-CO-O-CH

2 -CO-phenyl) 521 2 alpha -CH 3 4-(Tert-butyl)benzyl -H 523 2 alpha -CH 3 7-Methoxy-coumarin-4-yi-methyl -H 524 2 alpha -CH 3 4-Methylbenzyl -H 525 2 alpha -CH 3 4-Methylsulfonylbenzyl -H 526 12 alpha -CH 3 4-Phenoxy-butyl -H 527 2 alpha -CH 3 Benzof urazan-5-yi-methyl -H 528 2 alpha -CH 3 2-(6-Amino-9H-purin-9-yi)-ethyl -H 529 2 alpha -CH 3 3-Cyano-benzyl -H 530 2 alpha -CH 3 2-Cyano-benzyl -H 531 2 alpha -CH 3 4-Cyano-benzyl -H 532 2 alpha -CH 3 Benzoic acid 2-ethyl ester /-H I___ __ -CH 2

-CH

3 -O-CO-phenyl 534 2 alpha -CH 3 Cyclopropylmethyl -H 536 2 alpha -CH 3 4-(1,3-bioxo-1,3-dihydro-isoindol-2-yl)-butyI

-H

WO 2006/125800 PCT/EP2006/062587 124 Table 7: Intermediates of the general formula XX (carbamate derivatives) 0 H H~ H C-(XX) PG ON 0-R 2 H C15 PG or RMS HPLC No. n stereo R 2 M/Z Rt [min]_ 538 1 alpha -H Isobutyl 400 5.58 539 1 alpha -H 4-Nitro-benzyl 478 5.62 5 Table 8: Intermediates of the general formula XXII (sulfamate derivatives) O H C-(XXII) PGN " 0 0 N"10 OH -O-R2 C15 PG or MS HPLC No. n stero R2 m/z Rt stereo M/Z[min]_ 540 1 alpha -CH 3 Ethyl 541 1 alpha -CH 3 Butyl 542 1 alpha -CH 3 Benzyl 543 1 alpha -CH 3 Phenyl Table 9: Intermediates of the general formula XXIII ("retro"-amide derivatives) O H C-(XXIII) PG H 10 0 WO 2006/125800 PCT/EP2006/062587 125 C15 PG or 2 MS HPLC stereo RI /2 m/z 544 1 alpha -CH 3 3,5-Bis-trifluoromethyl-phenyl 553.21 4.73 548 1 alpha -CH 3 3-Methoxy-phenyl 447.24 4.27 551 1 alpha -CH 3 4-Hexyloxy-phenyl 517.32 5.25 552 1 alpha -CH 3 4-Trifluoromethyl-phenyl 485.22 4.59 554 1 alpha -CH 3 Phenoxy-methyl 447.24 4.31 557 1 alpha -CH 3 Ethyl 369.23 3.81 559 1 alpha -CH 3 2-Cyclopentyl-ethyl 437.29 4.56 561 1 alpha -CH 3 Furan-2-yl 407.21 4.03 562 1 alpha -CH 3 Thiophen-2-yl-methyl 437.2 4.15 565 1 alpha -CH 3 Acetic acid methyl ester / -CH 2 -CO-0-CH 3 413.22 3.79 567 1 alpha -CH 3 2,4,5-Trifluorophenyl 471.2 4.51 569 1 alpha -CH 3 1-Phenyl-5-trifluoromethyl-1H-pyrazol-4-yl 551.24 4.53 570 1 alpha -CH 3 Adamantan-1-yl 475.31 4.89 574 4 alpha -H 2-methoxy-phenyl 475.27 5.77 577 4 alpha -H 4-Chloro-phenyl 479.22 5.95 580 4 alpha -H methoxymethyl 413.26 5.01 584 4 alpha -H 1-ethoxy-1-oxo-propan-3-yl 469.28 5.25 588 4 alpha -H naphthalen-2-yl 495.28 6.04 593 4 alpha -H Benzo[b]thiophene-2-yl 501.23 6.09 601 3 alpha -H benzyl 445.26 3.69 602 3 alpha -H Phenethyl 459.28 3.78 606 3 alpha -H 3-Cyano-phenyl 456.24 3.72 609 3 beta -CH 3 2,4-Dichloro-phenyl 513.18 6.74 622 3 beta -CH 3 4-Cyano-phenyl 470.26 6.24 625 3 beta -CH 3 3,5-Dichloro-phenyl 513.18 7.16 627 3 beta -CH 3 Benzyloxy-methyl 489.29 6.53 629 4 beta -CH 3 3,4-Difluoro-phenyl 495.26 6.84 635 4 beta -CH 3 2-bromo-phenyl 537.19 6.7 637 4 beta -CH 3 3-Chloro-phenyl 493.24 6.97 641 4 beta -CH 3 4-methoxy-phenyl 489.29 6.54 645 4 beta -CH 3 2,2-dimethyl-propyl 453.32 6.72 648 4 beta -CH 3 cyclohexyl 465.32 6.82 650 4 beta -CH 3 naphthalen-1-yl 509.29 6.93 653 3 alpha -H 3,4-Dichlorophenyl 500 4.17 655 4 alpha -H 4-Fluorobenzyl 478 5.72 657 4 alpha -H 2,4-Difluorophenyl 482 5.86 658 5 beta -CH 3 Phenyl 474 6.80 660 5 beta -CH 3 4-Fluorophenyl 492 6.68 Table 10: Intermediates of the general formula XXIV ("retro"-sulfonamide derivatives) 0 H) PG H H C-(XXIV) H S-R 2 0 WO 2006/125800 PCT/EP2006/062587 126 C15 PG or 2 MS HPLC stereo RI /2 m/z 661 1 alpha -H Naphthalene-2-yl 489.2 5.75 663 1 alpha -H Quinoline-8-yl 490.19 5.41 666 1 alpha -H 4-(N-acetyl)-amino-phenyl 496.2 4.83 668 1 alpha -H 4-methoxy-phenyl 469.19 5.35 673 1 alpha -H 3.4-Dichloro-phenyl 507.1 5.98 676 1 alpha -H 3-Chloro-phenyl 473.14 5.67 704 3 beta -CH 3 4-nitro-phenyl 526.21 4.54 706 3 beta -CH 3 benzyl 495.24 4.51 707 3 beta -CH 3 propyl 447.24 4.34 713 3 beta -CH 3 2.5-Dichloro-thiophene-3-yl 555.11 5.04 715 3 beta -CH 3 3-methyl-phenyl 495.24 4.67 716 3 beta -CH 3 3.4-dimethoxy-phenyl 541.25 4.37 717 3 beta -CH 3 4-Benzenesulfonyl-thiophene-2-yl 627.18 4.59 720 4 beta -CH 3 Thiophene-2-yl 501.2 4.65 723 4 beta -CH 3 4-Fluoro-phenyl 513.23 4.74 727 4 beta -CH 3 3-trifluoromethyl-phenyl 563.23 4.97 728 4 beta -CH 3 3.5-Bis-trifluoromethyl-phenyl 631.22 5.23 729 4 beta -CH 3 2.5-dimethoxy-phenyl 555.27 4.72 731 4 beta -CH 3 4-trifluoromethoxy-phenyl 579.23 5.03 739 5 beta -CH 3 4-Methyl-phenyl 524 6.91 Table 11: Intermediates of the general formula XXV (sulfonylurea derivatives) 0 PG H H OC-(XXV) N N R2 H '-' S_ 0 0

R

2 C15 PG or MS HPLC No. n stereo 2 m/z 740 2 alpha -CH 3 Phenyl 741 2 alpha -CH 3 4-Chloro-phenyl 742 2 alpha -CH 3 4-Methyl-phenyl 743 2 alpha -CH 3 2-Methyl-phenyl 5 Table 12: Intermediates of the general formula XXVI ("retro"-carbamate derivatives) 0 H PG- H H n H C-(XXVI) 0 0 N-R 2

O

WO 2006/125800 PCT/EP2006/062587 127 No. C15 PG or MS HPLC stereo R 1 m/2 m/ 744 3 beta -CH 3 2,4-Dichloro-phenyl 529 5.52 745 3 beta -CH 3 4-Trifluoromethyl-phenyl 529 5.18 747 3 beta -CH 3 3-Cyano-phenyl 486 4.74 748 3 beta -CH 3 Benzo[1,3]dioxol-5-yl- 505 4.68 751 4 beta -CH 3 3-Fluoro-phenyl 493 5.1 755 4 beta -CH 3 2-benzoic acid methyl ester 533 5.67 761 5 beta -CH 3 3-Nitro-phenyl 534 5.21 764 5 beta -CH 3 3.4-Dichloro-benzyl 571 5.48 767 6 beta -CH 3 4-benzoic acid ethyl ester 553 5.56 769 6 beta -CH 3 Naphthalen-1-yl 561 6.12 773 6 beta -CH 3 3,4-Dichloro-phenyl 553 5.56 Table 13: Intermediates of the general formula XXVII ("retro"-ester derivatives) 0 H H H C-(XXVII) O0 R 2 0 C15 PG or MS HPLC No. stero R m/z stere m/Z[min] 774 4 beta -CH 3 Tert-Butyl 441 7.85 775 5 beta -CH 3 Tert-Butyl 455 8.07 5 Table 14: Intermediates of the general formula XXVIII (sulfonylcarbamate derivatives) 0 C-(XXVll) PG' H H ~ 0

R

2 01 ,0 N-S-N H/R4 0 C15 P& or MS RtL N.nstereo R 1 ___ 4 m/Z [min 790 3 beta -CH 3 2-(1H-indol-3-yI)-ethyl H 607 4.36 792 3 beta -CH 3 cyclohexyl H 546 4.59 795 3 beta -CH 3 morpholine-4-yl 534 3.96 797 4 beta -CH 3 4-methyl-piperazine-1-yi 561 3.57 802 4 beta -CH 3 methyl benzyl 582 4.84 805 5 beta -CH 3 benzyl H 582 4.64 WO 2006/125800 PCT/EP2006/062587 128 S _______TR2 r R4__________ 811 5 beta -CH 3 methyl butyl 562 5.09 817 6 beta -CH 3 butyl H 562 4.9 818 6 beta -CH 3 phenyl H 582 4.46 INTERMEDIATES 820 to 834 - alcohols The synthesis of the following estrone-alcohol derivatives of general formula XXXI is de 5 scribed in the section "Intermediates, Chapter IV - Compounds of formula XXXI". Intermediate No. 820: 15a-Hydroxymethyl-3-hydroxy-estra-1,3,5(10)-trien-17-one (XXXia-1a) Intermediate No. 821: 15a-Hydroxymethyl-3-methoxy-estra-1,3,5(10)-trien-17-one (XXXia-1b) Intermediate No. 822: 3-Benzyloxy-15a-hydroxymethyl-estra-1,3,5(10)-trien-17-one (XXXia-1c) 10 Intermediate No. 823: 3-Hydroxy-15p-(3-Hydroxypropyl)-estra-1,3,5(10)-trien-17-one (XXXIp-3a) Intermediate No. 824: 15-(3-Hydroxypropyl)-3-methoxyestra-1,3,5(10)-trien-17-one (XXXIp-3b) Intermediate No. 825: 3-Benzyloxy-15-(3-hydroxypropyl)-estra-1,3,5(10)-trien-17-one (XXXIp-3c) Intermediate No. 826: 3-Hydroxy-15p-(4-hydroxybutyl)-estra-1,3,5(10)-trien-17-one (XXXIp-4a) Intermediate No. 827: 15-(4-Hydroxybutyl)-3-methoxy-estra-1,3,5(10)-trien-17-one (XXXIp-4b) 15 Intermediate No. 828: 3-Benzyloxy-15-(4-hydroxybutyl)-estra-1,3,5(10)-trien-17-one (XXXIp-4c) Intermediate No. 829: 3-Hydroxy-15p-(5-Hydroxypentyl)-estra-1,3,5(10)-trien-17-one (XXXIp-5a) Intermediate No. 830: 15 -(5-Hydroxypentyl)-3-methoxy-estra-1,3,5(10)-trien-17-one (XXXIp-5b) Intermediate No. 831: 3-Benzyloxy-15 -(5-hydroxypentyl)-estra-1,3,5(10)-trien-17-one (XXXIp-5c) Intermediate No. 832: 3-Hydroxy-15p-(6-hydroxyhexyl)-3-estra-1,3,5(10)-trien-17-one (XXXIp-6a) 20 Intermediate No. 833: 15 -(6-Hydroxyhexyl)-3-methoxy-estra-1,3,5(10)-trien-17-one (XXXIp-6b) Intermediate No. 834: 3-Benzyloxy-15 -(6-hydroxyhexyl)-estra-1,3,5(10)-trien-17-one (XXXIp-6c) Table 15: Intermediates of the general formula XXX (ether derivatives) O H C-(XXX) H H n PG OG1 O-R2 C15 PG or p2 MS HPLC Rt stereo R m/z [min] 835 3 beta -CH 3 Methyl 374 6.8 836 4 beta -CH 3 Phenyl 450 7.77 25 WO 2006/125800 PCT/EP2006/062587 129 Examples In order to more fully illustrate the nature of the invention and the manner of practicing the same, the following examples are presented, but they should not be taken as limiting. 5 I. Compounds carrying an additional substituent in C2 position of the steroidal core EXAMPLE 1: N-Benzyl-4-(2-ethyl-3-hydroxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyramide O H HOP HOO 10 Example 1 was obtained from intermediate compound (lVb-(C2-C)-3a) by amid coupling ac cording to Flow Diagram Ib: Compound (lVb-(C2-C)-3a) (100 mg, 0.26 mmol) was dissolved in a mixture of EtOAc (35 ml), benzyl amine (0.26 mmol), TEA (0.52 mmol) and propylphosphonic acid anhydride in EtOAc (T3P) (50 w/w %, 0.52 mmol) under N 2 atmosphere at 0*C. After stirring for 2h at ambient temperature, the reaction mixture was poured into water (50 ml) and diluted with EtOAc 15 (25 ml). The aqueous layer was neutralized to pH 8 with aq NaHCO 3 , separated and extracted with EtOAc. The combined organic layers were washed with water and dried over Na 2

SO

4 . The organic layer was concentrated in vacuo yielding Compound No. 1 (56 mg, 0.12 mmol, 46 %) after column chromatography (Si0 2 , DCM/MeOH = 100/0 to 95/5). 20 'H-NMR (300 MHz, CDCl 3 ): 6 0.99 (s, 3H, Steroid-CH 3 ), 1.22 (t, J = 7.4 Hz, 3H, Ethyl), 1.3 1.8 (m, 11 H, Steroid), 2.2-2.42 (m, 8H, Steroid), 2.60 (q, J = 7.4 Hz, 2H, Ethyl), 2.8-2.88 (m, 2H, Steroid), 4.44 (d, J = 5.8 Hz, 2H, CH 2 -Ph), 4.64 (bs, 1 H, OH), 5.67 (bs, 1 H, NH), 6.53 (s, 1 H, Ster oid-Ar-H), 7.03 (s, 1H, Steroid-Ar-H), 7.23-7.34 (m, 5H, Bn) ppm. 25 EXAMPLE 2: N-Benzyl-4-(3-hydroxy-17-oxo-2-propyl-estra-1,3,5(10)-trien-15p-yl)-butyramide O H HOP Example 2 was obtained from intermediate compound (lVb-(C2-G)-3a) by amid coupling ac cording to Flow Diagram Ib: Compound (lVb-(C2-G)-3a) (500 mg, 1.25 mmol) was dissolved in a mixture of EtOAc (25 ml), benzyl amine (2.50 mmol), TEA (3.75 mmol) and propylphosphonic acid WO 2006/125800 PCT/EP2006/062587 130 anhydride in EtOAc (T3P) (50 w/w %, 1.50 mmol) under N 2 atmosphere. After the reaction mixture had been stirred at ambient temperature for 1h, it was stirred at 45 *C for 16h. The reaction mixture was allowed to reach ambient temperature, poured into water (50 ml) and diluted with EtOAc (25 ml). The aqueous layer was separated and extracted with EtOAc. The combined organic layers 5 were, washed with aq. 1 M HCI, washed with brine and dried over Na 2

SO

4 . The organic layer was concentrated in vacuo yielding Compound No. 2 (370 mg, 0.756 mmol, 60%) after column chro matography (SiO 2 , DCM/MeOH = 97.5/2.5). 'H-NMR (300 MHz, CDCl 3 ): 6 0.96 (t, 3H), 0.98 (s, 3H), 1.3-1.6 (m, 4H), 1.6-1.8 (m, 7H), 10 1.90 (d, 1H), 2.00 (d, 1H, broad), 2.2-2.5 (m, 7H), 2.58 (t, 2H), 2.7-2.9 (m, 2H), 4.23 (d, 2H), 4.97 (s, 1 H, broad), 5.72 (t, 1 H, broad), 6.50 (s, 1 H), 7.00 (s, 1 H), 7.2-7.3 (m, 5H) ppm. EXAMPLE 3: N-Benzyl-4-(3-hydroxy-2-(2-methoxy-ethyl)-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide 0 H OH HO 15 0 Example 3 was obtained from intermediate compound (lVb-(C2-F)-3a) by amid coupling ac cording to Flow Diagram Ib using the procedure as described for Example 1. 'H-NMR (300 MHz, CDCl 3 ): 6 0.99 (s, 3H, Steroid-CH 3 ), 1.2-2.0 (m, 11H, Steroid), 2.2-2.42 20 (m, 7H, Steroid), 2.84 (m, 4H, Steroid), 3.41 (s, 3H, OMe), 3.67 (m, 2H, OCH 2 ), 4.44 (d, J = 5.5 Hz, 2H, CH 2 -Ph), 5.71 (bm, 1 H, OH or NH), 6.67 (s, 1 H, Steroid-Ar-H), 6.94 (s, 1 H, Steroid-Ar-H), 7.25 7.34 (m, 5H, Bn), 7.96 (s, 1H, OH or NH) ppm. EXAMPLE 4: N-Benzyl-4-(3-hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-butyramide 0 H HO 25 Example 4 was obtained starting from intermediate compound (lVb-(C2-B)-3a) by amide coupling according to Flow Diagram Ib. A solution of the 0.07 mmol (lVb-(C2-B)-3a), 0.077 mmol HOBT, 0.231 mmol NMM and 0.154 mmol EDCI in 5 ml DCM were added to 0.07 mmol of benzyl amine. The reaction mixture was stirred for 24 h at ambient temperature. The solvent was removed 30 in vacuo at 40*C. Than 4 ml EtOAc and 4 ml water were added. After vigorous stirring for 2 min, WO 2006/125800 PCT/EP2006/062587 131 the organic phase was separated, dried with Na 2

SO

4 and evaporated in vacuo at 40*C. The crude product was treated with 2 ml THF, 10 mg LiOH and 0.5 ml water. After evaporation and further ex traction (EtOAc and 0.1 M KHSO 4 ), 50 mg trisaminoeethlyamine polymer bound were added. After filtration and evaporating to dryness the compound No. 4 was obtained (HPLC Rt = 3.79). 5 EXAMPLE 5: 2-Ethyl-3-hydroxy-15p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one 0a H O H H N HO O Example 5 was prepared starting from intermediate compound (lVb-(C2-C)-3a), which was converted into the desired amid by amid coupling with morpholine according to Flow Diagram Ib 10 and as described above for Example 2 (Compound (lVb-(C2-C)-3a) (110 mg, 0.28 mmol), EtOAc (30 ml), morpholine (0.28 mmol), TEA (0.57 mmol), T3P (0.34 mmol). Compound No. 5 (68 mg, 0.15 mmol, 54 %) obtained after column chromatography (Si0 2 , DCM/MeOH = 100/0 to 95/5). 1H-NMR (300 MHz, CDCl 3 ): 6 1.01 (s, 3H, Steroid-CH 3 ), 1.22 (t, J = 7.5 Hz, 3H, Ethyl), 1.3 15 2.0 (m, 11H, Steroid), 2.2-2.42 (m, 7H, Steroid/Morpholine), 2.60 (q, J = 7.7 Hz, 2H, ethyl), 2.82 2.90 (m, 2H, Steroid), 3.44-3.50 (m, 2H), 3.6-3.70 (m, 6H, Morpholine), 4.61 (s, 1H, OH), 6.53 (s, 1H, Steroid-Ar-H), 7.04 (s, 1H, Steroid-Ar-H) ppm. EXAMPLE 6: 3-Hydroxy-15p-(4-morpholin-4-yl-4-oxo-butyl)-2-propyl-estra-1,3,5(10)-trien-17-one 2 H O | H H No HO 20 0 Example 6 was prepared as described above for Example 2 starting from intermediate com pound (lVb-(C2-G)-3a), which was converted into the desired amid by amid coupling with mor pholine according to Flow Diagram Ib (Compound (lVb-(C2-G)-3a) (500 mg, 1.25 mmol), EtOAc (25 ml), morpholine (2.5 mmol), TEA (3.75 mmol), T3P (1.5 mmol). Compound No. 6 (225 mg, 25 0.481 mmol, 38 %) was obtained after column chromatography (Si0 2 , DCM/MeOH = 97.5/2.5). 'H-NMR (300 MHz, CDCl 3 ): 6 0.98 (t, 3H), 1.01 (s, 3H), 1.3-1.8 (m, 11H), 1.90 (d, 1H), 2.00 (d, 1H, broad), 2.2-2.5 (m, 7H), 2.35 (t, 2H), 2.8-3.0 (m, 2H), 3.45 (t, 2H), 3.6-3.70 (m, 6H), 5.30 (s, 1 H), 6.54 (s, 1 H), 7.00 (s, 1 H) ppm. 30 WO 2006/125800 PCT/EP2006/062587 132 EXAMPLE 7: 3-Hydroxy-2-(2-methoxy-ethyl)-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one O H O A N HO O Example 7 was prepared from intermediate compound (lVb-(C2-F)-3a) by amid coupling ac 5 cording to Flow Diagram Ib: Compound (IVb-(C2-F)-3a) (85 mg, 0.221 mmol) was dissolved in a mixture of EtOAc (40 ml), morpholine (0.24 mmol), TEA (0.44 mmol) and T3P in in EtOAc (50 w/w %, 0.26 mmol) under N 2 atmosphere at 0 *C. After stirring at ambient temperature for 16h, the re action mixture was poured into water (100 ml) and diluted with EtOAc (50 ml). The aqueous layer was neutralized to pH 8 with aq. NaHCO 3 , separated and extracted with EtOAc (3x 50 ml). The 10 combined organic layers were washed with water (50 ml) and dried over Na 2

SO

4 .The organic layer was concentrated in vacuo yielding Compound No. 7 (43 mg, 0.088 mmol, 40 %) after column chromatography (Si0 2 , DCM/MeOH = 99/1 to 94/6). 'H-NMR (300 MHz, CDCl 3 ): 6 1.00 (s, 3H, Steroid-CH 3 ), 1.2-2.05 (m, 9H, Steroid), 2.2-2.44 15 (m, 8H, Steroid + morpholine), 2.81 (m, 4H, Steroid), 3.40 (s, 3H, OMe), 3.45 (t, J = 4.7 Hz, 2H,

OCH

2 ), 3.57-3.72 (m, 8H, morpholine), 6.67 (s, 1H, Steroid-Ar-H), 6.94 (s, 1H, Steroid-Ar-H), 7.97 (s, 1H, OH or NH) ppm. EXAMPLE 8: 3-Hydroxy-2-methoxy-15p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one O H O /OD A AIN HO 20 O Example 8 was prepared starting from intermediate compound (lVb-(C2-B)-3a), which was converted into the desired amid by amid coupling with morpholine according to Flow Diagram lb and as described above for Example 4 using 0.07 mmol of (lVb-(C2-B)-3a) and 0.07 mmol mor pholine, yielding Compound No. 4. 25 1 3 C NMR (126 MHz, CHLOROFORM-d): 5 ppm 17.7 (q, 1 C) 25.1 (t, 1 C) 25.8 (t, 1 C) 26.8 (t, 1 C) 28.7 (t, 1 C) 30.9 (t, 1 C) 32.8 (t, 1 C) 33.9 (t, 1 C) 34.4 (d, 1 C) 36.0 (d, 1 C) 41.9 (t, 1 C) 42.7 (t, 1 C) 44.8 (d, 1 C) 45.9 (t, 1 C) 47.1 (s, 1 C) 52.8 (d, 1 C) 56.1 (d, 1 C) 66.6 (t, 1 C) 66.9 (t, 1 WO 2006/125800 PCT/EP2006/062587 133 C) 107.8 (d, 1 C) 114.6 (d, 1 C) 129.2 (s, 1 C) 131.4 (s, 1 C) 143.7 (s, 1 C) 144.7 (s, 1 C) 171.2 (s, 1 C) 220.9 (s, 1 C) 1H NMR (501 MHz, CHLOROFORM-d): 8 ppm 1.02 (s, 3 H) 1.32 - 1.85 (m, 7 H) 1.87 - 1.95 5 (m, 1 H) 1.98 - 2.06 (m, 1 H) 2.25 - 2.51 (m, 5 H) 2.75 - 2.92 (m, 2 H) 3.42 - 3.51 (m, 2 H) 3.57 3.72 (m, 6 H) 3.86 (s, 3 H) 5.52 (s, 1 H) 6.67 (s, 1 H) 6.78 (s, 1 H) EXAMPLE 9: 4-(2-Ethyl-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl)-butyramide H H S HH H N HO N 10 0 Example 9 was prepared as described above for Example 2 starting from intermediate com pound (IVb-(C2-C)-3a), which was converted into the desired amid by amid coupling with 2-amino 5-methylthiazole according to Flow Diagram Ib: (Compound (lVb-(C2-C)-3a) (730 mg, 1.89 mmol), EtOAc (150 ml), 2-amino-5-methylthiazole (1.89 mmol), TEA (3.79 mmol), T3P (2.27 mmol). Com 15 pound No. 9 (280 mg, 0.58 mmol, 31 %) was obtained after recrystallization from DCM. 'H-NMR (300 MHz, d-DMSO): 6 0.90 (s, 3H, Steroid-CH 3 ), 1.05 (t, J = 7.4 Hz, 3H, Ethyl), 1.2-1.4 (m, 4H, Steroid), 1.44-1.74 (m, 6H, Steroid), 1.82-1.93 (m, IH, Steroid), 2.1-2.7 (m, 14H, Steroid), 6.43 (s, 1 H, Steroid-Ar-H), 6.89 (s, 1 H, Steroid-Ar-H), 7.08 (d, J = 1.0 Hz, 1 H, Thiazol-H), 20 8.82 (bs, 1 H, NH or OH) , 11.82 (bs, 1 H, NH or OH) ppm. EXAMPLE 10: 4-(3-Hydroxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15p-yl)-N-(5-methyl-thiazol-2-yl)-butyramide 0 H H N 25 Example 10 was prepared starting from intermediate compound (lVb-(C2-B)-3a), which was converted into the desired amid by amide coupling according to Flow Diagram Ib and as described above for Example 4 using 0.07 mmol of (lVb-(C2-B)-3a) and 0.07 mmol 2-amino-5-methylthiazole, yielding Compound No. 10 (33.7mg, MS 484, Rt 3.86).

WO 2006/125800 PCT/EP2006/062587 134 FURTHER COMPOUNDS A variety of compounds numbered 11 to 28 and falling under the scope of general formula (1), in which X-A-Y represents -CO-NR 4 , R 1 represents H, R 1 4 represents -O-CH 3 ,C15 is substi 5 tuted in the P position and n is 3, were prepared by parallel chemistry using a reaction according to general flow diagram lb and as described in EXAMPLE 4. TABLE 16 0 H O %R2, HO H N-R4 R2 p4 No- MW HPLC Rt -N 4 [mi] R2 11 Cyclopropyl H 425.6 3.48 12 Cyclohexyl H 467.6 3.90 13 Benzo[1,3]dioxol-5-ylmethyl H 519.6 3.73 14 2-Pyridin-2-yl-ethyl H 490.6 3.43 15 Pyridin-3-yl-methyl H 476.6 3.36 16 2-Methoxy-ethyl H 443.6 3.41 17 2,4-Difluorobenzyl H 511.6 3.88 18 3,5-Dimethoxy-benzyl H 535.7 3.78 19 2-(7-Methyl-1H-indol-3-yl)-ethyl H 542.7 3.92 20 1-Methyl-1H-imidazol-4-ylmethyl H 479.6 3.18 21 Piperidin-1-yl 453.6 3.90 22 Methyl Benzyl 489.7 4.07 23 Ethyl Ethyl 441.6 3.84 24 Methyl 2-(3,4-Dimethoxy-phenyl)- 563.7 3.87 ethyl 25 4-Isopropyl-piperazin-1-yl 496.7 3.19 26 3,4-Difluoro-phenyl H 497.6 4.15 27 3-Chloro-phenyl H 496.0 4.24 28 3-Trifluoromethoxy-phenyl H 545.6 4.40 10 A variety of compounds numbered 29 to 89 and falling under the scope of general formula (1), in which X-A-Y represents -CO-NR 4 , R 1 represents H, and n is 3, were prepared by parallel chemistry using a reaction according to general flow diagram lb. 15 Synthesis Protocol: 0.07 mmol of the individual amine was weight out into a reaction flask. A solution of 0.07 mmol of the respective steroidal building block (lVb-(C2-G)-3a), (lVa-(C2-D)-3a), and (lVa-(C2-B)-3a) in 5 ml DCM were added. Then, 0.077 mmol polymer bound HOBT, 0.231 WO 2006/125800 PCT/EP2006/062587 135 mmol polymer bound NMM and 0.154 mmol polymer bound EDCI were added. The reaction mix ture was stirred for 24 h at ambient temperature. Afterwards, the reaction mixture was filtrated, washed twice with 1 ml DCM and evaporated to dryness. The crude product was treated with 2 ml THF, 10 mg LiOH and 0.5 ml water. After evaporation and further extraction (EtOAc and 0.1 M 5 KHSO 4 ) approx. 50 mg trisaminoeethlyamine polymer bound were added yielding the desired product after filtration and evaporating to dryness. TABLE 17 O H H H N-R4 HO

R

2 jg4 P14 15 R R4HPLC Rt No. R' 4 C15 R4~i MW H[mirnP stereo -N [min] R2 29 propyl beta cyclohexyl H 479.7 6.09 30 propyl beta Benzo[1,3]dioxol-5-ylmethyl H 531.7 5.90 31 propyl beta 2-pyridin-2-yl-ethyl H 502.7 5.46 32 propyl beta pyridin-3-ylmethyl H 488.7 5.36 33 propyl beta 3,5-Dimethoxy-benzyl H 547.7 5.96 34 propyl beta 2-(7-methyl-1H-indol-3-yI)-ethyl H 554.8 6.12 35 propyl beta 1-methyl-1H-imidazol-4-ylmethyl H 491.7 5.12 36 propyl beta piperidin-1-yl 465.7 6.05 37 propyl beta methyl benzyl 501.7 6.27 38 propyl beta 2-(3,4-Dimethoxy-phenyl)-ethyl H 575.8 6.01 39 propyl beta 4-isopropyl-piperazin-1-yl 508.7 5.10 40 propyl beta 1H-indazol-6-yi H 513.7 6.26 41 propyl beta 2-methoxy-ethyl H 455.3 5.78 42 propyl beta 2,4-difluorobenzyl H 523.3 6.50 43 ethoxy alpha cyclopropyl H 439.6 5.06 44 ethoxy alpha cyclohexyl H 481.7 5.67 45 ethoxy alpha Benzo[1,3]dioxol-5-ylmethyl H 533.7 5.49 46 ethoxy alpha 2-pyridin-2-yi-ethyl H 504.7 4.98 47 ethoxy alpha pyridin-3-ylmethyl H 490.6 4.89 48 ethoxy alpha benzyl H 489.7 5.57 49 ethoxy alpha 2-methoxy-ethyl H 457.6 4.93 50 ethoxy alpha 2,4-difluorobenzyl H 525.6 5.70 51 ethoxy alpha 3,5-Dimethoxy-benzyl H 549.7 5.55 52 ethoxy alpha 7-methyl-1H-indol-3-yl H 556.7 5.70 53 ethoxy alpha 1-methyl-1H-imidazol-4-ylmethyl H 493.6 4.58 54 ethoxy alpha morpholin-4-yl 469.6 5.07 55 ethoxy alpha piperidin-1-yl 467.6 5.63 56 ethoxy alpha methyl benzyl 503.7 5.89 57 ethoxy alpha 2-(3,4-Dimethoxy-phenyl)-ethyl H 577.8 5.60 WO 2006/125800 PCT/EP2006/062587 136

R

2 N. R4 C15 R HPLC IRt No. R" stereo -N R4 [min] R2D 58 ethoxy alpha 4-isopropyl-piperazin-1-yl 510.7 4.56 59 ethoxy alpha 1H-indazol-6-yl H 515.7 5.88 60 ethoxy alpha Benzo[1,3]dioxol-5-yl H 519.6 5.63 61 ethoxy alpha 3-Cyano-phenyl H 500.6 5.74 62 ethoxy alpha 3,4-bifluoro-phenyl H 511.6 5.98 63 ethoxy alpha 5-methyl-thiazol-2-yl H 496.7 5.58 64 ethoxy alpha ethyl ethyl 455.3 5.98 65 ethoxy alpha 3-chloro-phenyl H 509.2 6.56 66 methoxy alpha cyclopropyl H 425.6 4.78 67 methoxy alpha cyclohexyl H 467.6 5.42 68 methoxy alpha Benzo[1,3]dioxol-5-ylmethyl H 519.6 5.25 69 methoxy alpha 2-pyridin-2-yl-ethyl H 490.6 4.72 70 methoxy alpha pyridin-3-ylmethyl H 476.6 4.63 71 methoxy alpha benzyl H 475.6 5.32 72 methoxy alpha 2-methoxy-ethyl H 443.6 4.65 73 methoxy alpha 2,4-difluorobenzyl H 511.6 5.46 74 methoxy alpha 3,5-Dimethoxy-benzyl H 535.7 5.31 75 methoxy alpha 7-methyl-1H-indol-3-yl H 542.7 5.48 76 methoxy alpha 1-methyl-1H-imidazol-4-ylmethyl H 479.6 4.30 77 methoxy alpha morpholin-4-yl 455.6 4.79 78 methoxy alpha piperidin-1-yl 453.6 5.35 79 methoxy alpha methyl benzyl 489.7 5.63 80 methoxy alpha ethyl ethyl 441.6 5.29 81 methoxy alpha 2-(3,4-Dimethoxy-phenyl)-ethyl H 563.7 5.35 82 methoxy alpha 4-isopropyl-piperazin-1-yl 496.7 4.30 83 methoxy alpha 1H-indazol-6-yl H 501.6 5.63 84 methoxy alpha 5-methyl-thiazol-2-yl H 482.6 5.34 85 methoxy alpha 3,4-dihydroxybenzyl H 507.3 4.87 86 methoxy alpha Benzo[1,3]dioxol-5-yl H 505.3 5.71 87 methoxy alpha 3-Cyano-phenyl H 486.3 5.85 88 methoxy alpha 3,4-bifluoro-phenyl H 497.2 6.13 89 methoxy alpha 3-chloro-phenyl H 495.2 6.27 II. Compounds carrying a substitution of the C17 oxo function of the steroidal core 5 EXAMPLE 90: 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -morpholin-4-yl-butan-1 -one F F H O HO'

O

WO 2006/125800 PCT/EP2006/062587 137 Example 90 was prepared from the Intermediate No. 1 (3-Hydroxy-15p-(4-morpholin-4-yl-4 oxo-butyl)-estra-1,3,5(10)-trien-17-one) according to the reaction depicted in Section D-(I)-(b): To a solution of the estron derivative (106 mg; 250 pmol) in Deoxofluor (0.96 ml; 5.00 mmol) a drop of ethanol was added; the solution was stirred at RT for 5 d. Subsequently, DCM (10 ml) was added 5 and the product was hydrolyzed by addition of sat NaHCO 3 solution under ice cooling. For work up, the organic phase was separated off, and the remaining water phase was extracted with DCM. The combined DCM fractions were dried over MgSO 4 . After evaporation and subsequent purification using column chromatography (DCM/Ether 1:1), 81 mg of a colourless solid were obtained (MW 489.64). 10 1 3 C NMR (126 MHz, CHLOROFORM-d): 5 ppm 17.0 (q, J(cF), 1 C) 24,5 (t, 1 C) 25.0 (t, 1 C) 27,4 (t, 1 C) 29.3 (t, J(cF),1 C) 30.7 (t, 1 C) 31.7 (t, 1 C) 32,9 (d, J(CF),1 C) 34.4 (t, 1 C) 35.9 (d, 1 C) 39.7-40.5 (t, J (C,F),1 C) 42.0 (t, 1 C) 44.1 (d, 1 C) 45.2 (t, 1 C) 46,1 (s, J(cF), 1 C) 50,3 (d, J(CF), 1 C) 66.7 (t, 1 C) 67.0 (t, 1 C) 112.7 (d, 1 C) 115.3 (d, 1 C) 126.0 (d, 1 C) 132.3 (s, 1 C) 138.0 (s, 1 C) 15 153.9 (s, 1 C) 171.5 (s, 1 C) 'H NMR (501 MHz, CHLOROFORM-d): 8 ppm 0.99 (s, 3 H) 1.23 - 2.5 (m, 18 H) 2.82 (m, 2 H) 3.43 - 3.52 (m, 2 H) 3.59 - 3.73 (m, 6 H) 5.66 (br. s., 1 H) 6.57 (d, J=2.55 Hz, 1 H) 6.63 (dd, J=8.5, 2.5 Hz, 1 H) 7.10 (d, J=8.5 Hz, 1 H) 20 EXAMPLE 91: 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-1 -morpholin-4-yl-butan-1 -one F F H 0 H H ' N 0 Example 91 was prepared from the Intermediate No. 40 named 3-Hydroxy-15a-(4 25 morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one as described for Example 90. 13 C NMR (126 MHz, CHLOROFORM-d): 8 ppm 14.9 (q, J(cF)= 3

.

89 Hz, 1 C) 23.8 (t, 1 C) 26.2 (t, 1 C) 27.6 (t, 1 C) 28.6 (t, J(C,F)= 4 .67 Hz, 1 C) 29.7 (t, 1 C) 33.2 (t, 1 C) 35.9 (d, J(C,F)=6.75 Hz, 1 C) 36.8 (t, 1 C) 39.4 (d, 1 C) 39.5 - 40.0 (t, J (C,F), 1 C) 42.1 (t, 1 C) 43.8 (d, 1 C) 46.1 (t, 1 C) 46.8 30 (s, J(cF)=1 9

.

98 Hz, 1 C) 53.1 (d, J(C,F)= 4 .15 Hz, 1 C) 66.6 (t, 1 C) 66.9 (t, 1 C) 113.1 (d, 1 C) 115.1 (d, 1 C) 126.8 (d, 1 C) 128.9 - 133.4 (s, J(cF), 1 C) 131.5 (s, 1 C) 137.5 (s, 1 C) 154.0 (s, 1 C) 171.8 (s, 1 C) WO 2006/125800 PCT/EP2006/062587 138 'H NMR (501 MHz, CHLOROFORM-d): 8 ppm 0.92 (s, 3 H) 1.19 - 1.36 (m, 3 H) 1.38 - 1.50 (m, 1 H) 1.51 - 1.83 (m, 7 H) 1.86 - 1.99 (m, 2 H) 2.13 - 2.23 (m, 1 H) 2.28 - 2.53 (m, 4 H) 2.70 2.83 (m, 2 H) 3.43 - 3.52 (m, 2 H) 3.59 - 3.73 (m, 6 H) 6.06 (br. s., 1 H) 6.55 (d, J=2.75 Hz, 1 H) 6.64 (dd, J=8.54, 2.75 Hz, 1 H) 7.12 (d, J=8.24 Hz, 1 H) 5 EXAMPLE 92: 4-(17-Fluoro-3-hydroxy-estra-1,3,5(10),16-tetraen-1 5p-yl)-1 -morpholin-4-yl-butan-1 -one F H O HO H7 N HOJD~O 0 Example 92 was isolated as by-product during the synthesis of Example No. 91. 10 'H NMR (501 MHz, CHLOROFORM-d): 8 ppm 0.99 (s, 3 H) 1.23 - 1.85 (m, 9 H) 1.93 - 2.00 (m, 1 H) 2.12 - 2.20 (m, 1 H) 2.25 - 2.48 (m, 5 H) 2.68 - 2.84 (m, 2 H) 3.44 - 3.53 (m, 2 H) 3.63 3.70 (m, 6 H) 4.83 - 4.87 (m, 1 H) 6.55 (d, J=2.4 Hz, 1 H) 6.63 (dd, J=8.5, 2.7 Hz, 1 H) 7.08 (d, J=8.5 Hz, 1 H) 15 1 3 C NMR (126 MHz, CHLOROFORM-d): 6 ppm 17.1 (q, J CF =4.2 Hz, 1 C) 23.3 (t, 1 C) 26.4 (t, 1 C) 27.8 (t, 1 C) 29.7 (t, 1 C) 32.9 (t, 1 C) 33.3 (t, 1 C) 34.2 (t, 1 C) 37.8 (d, 1 C) 40.4 (d, J C,F =5.7 Hz, 1 C) 42.1 (t, 1 C) 44.3 (s, J CF =20.5 Hz, 1 C) 44.4 (d, 1 C) 46.1 (t, 1 C) 57.9 (d, J CF =5.2 Hz, 1 C) 66.6 (t, 1 C) 66.9 (t, 1 C) 104.2 (d, J CF =8.0 Hz, 1 C) 112.9 (d, 1 C) 115.1 (d, 1 C) 126.3 20 (d, 1 C) 131.8 (s, 1 C) 137.4 (s, 1 C) 154.1 (s, 1 C) 170.7 (s, J C,F =289.9 Hz, 1 C) 172.0 (s, 1 C) EXAMPLE 93: 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl)-propionamide F F HN A _ S HO' N O H 25 Example 93 was prepared from the Intermediate IVp-2a-D1 F2 using amide coupling with 2 amino-5-methylthiazole according to general flow diagram lb and as described for synthesis of Ex ample 4.

WO 2006/125800 PCT/EP2006/062587 139 'H NMR (501 MHz, DMSO-d): 5 ppm 1.01 (s, 3 H) 1.28 - 1.37 (m, 2 H) 1.47 - 1.74 (m, 5 H) 1.86 - 1.96 (m, 1 H) 1.97 - 2.04 (m, 1 H) 2.06 - 2.22 (m, 3 H) 2.24 - 2.39 (m, 6 H) 2.40 - 2.48 (m, 1 H) 2.68 - 2.84 (m, 2 H) 6.47 (d, J=2.4 Hz, 1 H) 6.52 (dd, J=8.4, 2.6 Hz, 1 H) 7.01 - 7.05 (m, 1 H) 7.09 - 7.11 (m, 1 H) 8.96 - 9.03 (m, 1 H) 11.86 (s, 1 H) 5 1 3 C NMR (126 MHz, DMSO-d): 5 ppm 11.0 (q, 1 C) 16.6 - 16.7 (q, J C,F, 1 C) 24.5 (t, 1 C) 26.8 (t, 1 C) 26.8 (t, 1 C) 28.8 (t, 1 C) 30.4 (t, J C,F =4.9 Hz, 1 C) 33.4 (d, J C,F =6.7 Hz, 1 C) 34.2 (t, 1 C) 35.5 (d, 1 C) 38.5 - 38.8 (t, J C,F ,1 C) 43.7 (d, 1 C) 44.5 - 45.0 (s ,J C,F , 1 C) 49.7 (d, J C,F =4.9 Hz, 1 C) 112.6 (d, 1 C) 114.9 (d, 1 C) 125.6 (d, 1 C) 125.9 (s, 1 C) 130.1 (s, 1 C) 130.6 - 134.7 (s, J 10 C,F, 1 C) 134.6 (d, 1 C) 137.1 (s, 1 C) 155.0 (s, 1 C) 156.1 (s, 1 C) 170.7 (s, 1 C) EXAMPLE 94: 4-(17-Trifluoromethyl-3-hydroxy-estra-1,3,5(10),16-tetraen-1 5p-yl)-1 -morpholin-4-yl-butan-1 -one CF3 H O H H N HO'C' 15 Example 94 was prepared from intermediate Vp-3a-D-(1)-(d)-CF 3 by amide coupling accord ing to general flow diagram la: To the solution of Vp-3a-D-(l)-(d)-CF 3 in DCM, a large excess of the HOnig base N(iPr) 2 Et and morpholine was added. The solution was stirred over night at ambient temperature. After dilution with further DCM and washing twice with 1 M KHSO 4 , the organic layer was dried over Na 2

SO

4 and evaporated to dryness. The crude material was purified by flash chro 20 matography with DCM/EtOAc and by preparative HPLC yielding 15 mg of compound No. 95 as white solid. 13 C NMR (126 MHz, CHLOROFORM-d): 8 ppm 22.2 (q, 1 C) 24.7 (t, 1 C) 25.6 (t, 1 C) 27.3 (t, 1 C) 29.1 (t, 1 C) 29.3 (t, 1 C) 33.1 (t, 1 C) 35.1 (d, 1 C) 36.1 (t, 1 C) 42.1 (t, 1 C) 44.2 (d, 1 C) 25 44.6 (d, 1 C) 46.1 (t, 1 C) 46.3 (s, 1 C) 57.6 (d, I C) 66.7 (t, 1 C) 67.0 (t, 1 C) 112.7 (d, 1 C) 115.3 (d, 1 C) 122.4 - 124.8 (s, 1 C) 125.8 (d, 1 C) 132.5 (s, 1 C) 137.9 (s, 1 C) 138.5 (d, J=5.7 Hz, 1 C) 143.3 - 144.3 (s, 1 C) 153.9 (s, 1 C) 171.5 (s, 1 C) 'H NMR (501 MHz, CHLOROFORM-d): 6 ppm 1.14 (s, 3 H) 1.32 - 1.78 (m, 8 H) 1.84 (dd, 30 J=1 1.9, 7.3 Hz, 1 H) 1.95 - 2.04 (m, 2 H) 2.27 - 2.36 (m, 4 H) 2.57 - 2.64 (m, 1 H) 2.80 - 2.88 (m, 2 H) 3.44 - 3.51 (m, 2 H) 3.62 - 3.71 (m, 6 H) 5.40 - 5.73 (m, 1 H) 6.45 - 6.48 (m, 1 H) 6.58 (d, J=2.7 Hz, 1 H) 6.63 (dd, J=8.2, 2.7 Hz, 1 H) 7.09 (d, J=8.2 Hz, 1 H) WO 2006/125800 PCT/EP2006/062587 140 EXAMPLE 95: 4-(17-Difluoromethylene-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -morpholin-4-yl-butan-1 -one F F Z H O HO 0 Example 95 was prepared from intermediate Vp-3a-D-(I)-(a)=CF 2 by amide coupling accord 5 ing to general flow diagram la: To the solution of VP-3a-D-(l)-(a)=CF 2 in DCM, a large excess of the HOnig base N(iPr) 2 Et and morpholine was added. The solution was stirred over night at ambient temperature. After dilution with further DCM and washing twice with 1 M KHSO 4 , the organic layer was dried over Na 2

SO

4 and evaporated to dryness. The crude material was purified by flash chro matography with DCM/EtOAc and by preparative HPLC yielding 15 mg of compound No. 95 as 10 white solid. 'H NMR (501 MHz, CHLOROFORM-d): 8 ppm 1.05 (s, 3 H) 1.18 - 1.30 (m, 1 H) 1.32 - 1.81 (m, 7 H) 1.87 - 1.97 (m, 1 H) 2.03 - 2.15 (m, 2 H) 2.18 - 2.36 (m, 4 H) 2.53 - 2.68 (m, 1 H) 2.77 2.91 (m, 2 H) 3.43 - 3.53 (m, 2 H) 3.59 - 3.72 (m, 6 H) 5.53 (br. s., 1 H) 6.57 (d, J=2.44 Hz, 1 H) 15 6.63 (dd, J=8.39, 2.59 Hz, 1 H) 7.11 (d, J=8.24 Hz, 1 H) 1 3 C NMR (126 MHz, CHLOROFORM-d): 8 ppm 20.9 (q, J(C,F)= 2

.

6 0 Hz, 1 C) 25.3 (t, 1 C) 26.2 (t, 1 C) 27.5 (t, 1 C) 29.5 (t, 1 C) 31.0 (t, 1 C) 31.3 (t, 1 C) 33.1 (t, 1 C) 35.8 (d, 1 C) 37.7 (d, 1 C) 38.0 (t, J(cF)= 4 .15 Hz, 1 C) 42.1 (t, 1 C) 42.3 (s, J(C,F)= 2 .98 Hz, 1 C) 44.3 (d, 1 C) 46.1 (t, 1 C) 57.7 20 (d, 1 C) 66.7 (t, 1 C) 67.0 (t, 1 C) 99.2 (s, J(cF)=1 7

.

26 Hz, 1 C) 112.7 (d, 1 C) 115.3 (d, 1 C) 126.0 (d, 1 C) 132.5 (s, 1 C) 138.0 (s, 1 C) 148.3 - 153.0 (s, J(C,F),1 C ) 153.8 (s, 1 C) 171.7 (s, 1 C) EXAMPLE 96: 4-(17-Difluoromethylene-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-1 -morpholin-4-yl-butan-1 -one F F H 0 H H N HO 25 0 WO 2006/125800 PCT/EP2006/062587 141 Example 96 can be prepared from the Intermediate No. 40 named 3-Hydroxy-15a-(4 morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one of formula (Vlx-3a)-40 according to the re action depicted in Section D-(1)-(a) / 1. 5 EXAMPLE 97: 4-(17-Trifluoromethyl-3-hydroxy-estra-1,3,5(10),16-tetraen-1 5a-yl)-l -morpholin-4-yl-butan-1 -one

CF

3 H O IH H ~ N HO 0 Example 97 can be prepared from the Intermediate No. 40 named 3-Hydroxy-15a-(4 morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one of formula (Vlx-3a)-40 according to the re 10 action depicted in Section D-(1)-(d) / 3. EXAMPLE 98: 4-(17-Trifluoromethyl-3-hydroxy-estra-1,3,5(1 0)-trien-15a-yl)-1 -morpholin-4-yl-butan-1 -one

CF

3 H 0 H H N HO 0 15 Example 98 can be prepared from Example 16 according to the last reaction step depicted in Section D-(1)-(c) / 3. EXAMPLE 99: 4-(17-Difluoromethyl-2-ethyl-3-hydroxy-estra-1,3,5(10)-trien-15p-yl)-N-(5-methyl thiazol-2-yl)-butyramide CHF2 H H N 20 0 Example 99 can be prepared starting from Example 9 (4-(2-Ethyl-3-hydroxy-17-oxo-estra 1,3,5(10)-trien-15 -yl)-N-(5-methyl-thiazol-2-yl)-butyramide) as educt, according to the reaction de picted in Section D-(1)-(c) / 2.

WO 2006/125800 PCT/EP2006/062587 142 EXAMPLE 100: 4-(17-Difluoromethyl-3-hydroxy-estra-1,3,5(10),16-tetraen-1 5p-yl)-l -morpholin-4-yl-butan-1 -one CHF 2 H O A A N HO O Example 100 can be prepared starting from Example 95 (4-(17-Difluoromethylene-3 5 hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -morpholin-4-yl-butan-1 -one) according to the reaction scheme depicted in Section D-(I)-(d) / 2. FURTHER COMPOUNDS 10 A variety of compounds numbered 101 to 138 and falling under the scope of general formula (1), in which X-A-Y represents -CO-NR 4 , R 1 represents -H, R 14 represents -H, and the C17 keto function is replaced by a difluoro group, was prepared by parallel chemistry using a reaction ac cording to general flow diagram lb starting from the already fluorinated intermediates IVa-3a-D1 F2 and IVp-2a-D1F2, respectively. 15 Synthesis Protocol: 0.07 mmol of the individual amine was weight out into a reaction flask. A solution of 0.07 mmol of the respective steroidal building block (IVa-3a-D1F2 and IVp-2a-D1F2), 0.077 mmol HOBT, 0.231 mmol NMM and 0.154 mmol polymer bound EDCI in 5 ml DCM were added. The reaction mixture was stirred for 24 h at ambient temperature. The solvent was removed 20 in a vacuum centrifuge at 40*C. Than 4 ml EtOAc and 4 ml H 2 0 were added. The two phases were stirred vigorously for 2 min, than the organic phase was dried with Na 2

SO

4 and evaporated in a vacuum centrifuge at 40*C. After treatment of the crude product with 2 ml THF, 10 mg LiOH and 0.5 ml water, the solvent was evaporated and the residue further extracted (EtOAc and 0.1 M

KHSO

4 ). Then, 50 mg polymer bound trisaminoeethlyamine was added yielding after filtration and 25 evaporating to dryness the desired product. If still necessary, products were further purified by flash chromatography (4 g silica gel, eluent EtOAc / cyclohexane). TABLE 18: F F H H H( HO1 % N-R4 R2 WO 2006/125800 PCT/EP2006/062587 143 No. n C15 stereo R - R 4 MW Hm it -N11R2DM[mn 101 3 alpha Cyclopropyl H 417 5.9 102 3 alpha Cyclohexyl H 459 6.58 103 3 alpha Benzo[1,3]dioxol-5-ylmethyl H 511 6.3 104 3 alpha 2-Pyridin-2-yl-ethyl H 482 5.77 105 3 alpha Pyridin-3-yl-methyl H 468 5.67 106 3 alpha Benzyl H 467 6.41 107 3 alpha 2-Methoxy-ethyl H 435 5.76 108 3 alpha 2,4-Difluorobenzyl H 503 6.52 109 3 alpha 3,4-dihydroxy-benzyl H 499 5.65 110 3 alpha 3,5-Dimethoxy-benzyl H 527 6.37 111 3 alpha 2-(7-Methyl-1H-indol-3-yl)- H 534 6.53 ethyl 112 3 alpha 1-Methyl-1H-imidazol-4- H 471 5.33 1_ ylmethyl 113 3 alpha Piperidin-1-vl 445 6.65 114 3 alpha Methyl Benzyl 481 6.84 115 3 alpha Ethyl Ethyl 433 6.54 116 3 alpha Methyl 2-(3,4-bimethoxy- 555 6.52 1 ______ 1_________1___ phenyl)-ethyl _____ 117 3 alpha 4-Isopropyl-piperazin-1-yl 488 5.38 118 3 alpha Benzo[1,3]dioxol-5-yl H 497 6.51 119 3 alpha 5-methyl-thiazol-2-yl H 474 6.51 120 2 beta Cyclopropyl H 403 5.76 121 2 beta Cyclohexyl H 445 6.48 122 2 beta Benzo[1,3]dioxol-5-ylmethyl H 497 6.17 123 2 beta 2-Pyridin-2-yl-ethyl H 468 5.6 124 2 beta Pyridin-3-yl-methyl H 454 5.51 125 2 beta Benzyl H 453 6.28 126 2 beta 2-Methoxy-ethyl H 421 5.6 127 2 beta 3,4-dihydroxy-benzyl H 485 5.52 128 2 beta 3,5-Dimethoxy-benzyl H 513 6.25 129 2 beta 2-(7-Methyl-1H-indol-3-yl)- H 520 6.37 ethyl 130 2 beta 1-Methyl-1H-imidazol-4- H 457 5.17 ylmethyl 131 2 beta Piperidin-1-vl 431 6.47 132 2 beta Methyl Benzyl 467 6.72 133 2 beta Ethyl Ethyl 419 6.42 134 2 beta Methyl 2-(3,4-bimethoxy- 541 6.4 1 ______ 1____________ phenyl)-ethyl _____ 135 2 beta 4-Isopropyl-piperazin-1-yl 474 5.18 136 2 beta Benzo[1,3]dioxol-5-yl H 483 6.37 137 2 beta 5-methyl-thiazol-2-yl H 433 5.82 138 2 beta 2-methoxy-ethyl 2-methoxy-ethyl 479.6 WO 2006/125800 PCT/EP2006/062587 144 III. Compounds with a heterocyclus fused to the steroidal D-ring EXAMPLES 151 to 165 were prepared from the corresponding intermediates (e.g. No. 1, 3A, 39, 1, 40 etc.) using the reaction scheme as depicted in SECTION D-(II). Alternatively, depending 5 on the nature of the C15 side chain, some of the reaction steps had to be carried out after having introduced the heterocyclic ring system, i.e. the 15,16-unsaturated intermediate (X) was derivatized to the appropriate acid or alkenyl intermediate (see e.g. SCHEMES 7B, 7C, 8A and 8B). Then, the heterocyclic ring system was introduced including the C16-C17 carbon atoms attached to the D ring. The so-obtained intermediates were then used for further modification and amidation of the 10 C15 side chain (introduction of the R2/R4 substituents). Finally the protection group in C3 position was cleaved off. EXAMPLES 151 and 152: N-Benzyl-4-(3-hydroxy-(1 7,16-c)-(1'-methyl)-pyrazolyl-estra-1,3,5(1 0)-trieno-1 5p-vl)-butyramide 15 N-Benzyl-4-(3-hydroxy-(1 7,16-c)-(2'-methyl)-pyrazolyl-estra-1,3,5(1 0)-trieno-1 5p-vl)-butyramide N N''N H H HO HO O O Starting from intermediate compound Xc, an allyl side chain was introduced into C1 5 position using 1,4-addition of allylbromide according to step 1 of SCHEME 7C, followed by construction of 20 the pyrazol-ring according to D-(II)-(a). Ringclosure with methyl hydrazine gave a mixture of the corresponding isomers. Conversion of the allyl into the N-Benzyl-butyramide side chain was per formed according to steps 2 - 4 of SCHEME 7C and to the reaction as depicted in general flow dia gram lb by reaction with benzylamine. Finally the obtained isomers were separated by preparative HPLC. 25 EXAMPLE 151: 'H-NMR (300 MHz, CDCl 3 ): 6 1.10-1.20 (s, 3H), 1.20-2.32 (m, 17H), 2.68 2.88 (m, 3H), 3.72-3.80 (s, 3H), 4.24-4.40 (dd, 2H), 6.48-6.52 (s, 1 H), 6.52-6.60 (d, 1 H), 6.96-7.08 (d, 1 H), 7.08-7.28 (m, 6H). 30 EXAMPLE 152: 1H-NMR (300 MHz, CDCl 3 ): 6 1.08-1.16 (s, 3H), 1.16-2.40 (m, 17H), 2.68 2.88 (m, 3H), 3.72-3.84 (s, 3H), 4.24-4.44 (dd, 2H), 6.44-6.54 (s, 1H), 6.54-6.60 (d, 1H), 7.00-7.12 (d, 1H), 7.12-7.32 (m, 6H).

WO 2006/125800 PCT/EP2006/062587 145 EXAMPLES 153 and 154: 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-(1'-methyl)-pyrazole 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-(2'-methyl)-pyrazole N N H O H O HA 0 N H 0 N O O 5 Examples 153 and 154 were prepared according to the procedure described for Examples 151 and 152 using morpholine as amine for the amide coupling step. EXAMPLE 153: 1H-NMR (300 MHz, CDCl 3 ): 6 1.04-1.20 (s, 3H), 1.24-1.84 (m, 9H), 2.00 2.52 (m, 8H), 2.88-2.96 (m, 3H), 3.40-3.70 (m, 8H), 3.70-3.92 (s, 3H), 6.22-6.44 (m, 2H), 6.96-7.12 10 (d, 1H), 7.20-7.28 (s, 1H). EXAMPLE 154: 1H-NMR (300 MHz, CDCl 3 ): 6 1.16-1.22 (s, 3H), 1.22-1.88 (m, 9H), 2.04 2.56 (m, 8H), 2.76-2.96 (m, 3H), 3.48-3.70 (m, 8H), 3.72-3.84 (s, 3H), 6.48-6.60 (m, 2H), 7.00-7.12 (d, 1 H), 7.16-7.24 (s, 1 H). 15 EXAMPLES 155 and 156: N-Benzyl-4-(3-hydroxy-(1 7,16-c)-(1'-methyl)-pyrazolyl-estra-1,3,5(1 0)-trieno-1 5a-yl)-butyramide N-Benzyl-4-(3-hydroxy-(1 7,16-c)-(2'-methyl)-pyrazolyl-estra-1,3,5(1 0)-trieno-1 5a-yl)-butyramide N- N

\N

H H HH HP I HP I N HHN HO HO 0 0 20 Starting from intermediate compound Xc, an allyl side chain was introduced into C15 position using 1,2-addition of allylbromide and subsequent rearrangement with potassium hydride according to steps 1 and 2 of SCHEME 8B, followed by construction of the pyrazol-ring according to D-(II)-(a). Ringclosure with methyl hydrazine gave a mixture of the corresponding isomers. Conversion of the allyl into the N-Benzyl-butyramide side chain was performed according to steps 3 - 5 of SCHEME 25 8B and to the reaction as depicted in general flow diagram lb by reaction with benzylamine. Finally the obtained isomers were separated by preparative HPLC.

WO 2006/125800 PCT/EP2006/062587 146 EXAMPLE 155: 1H-NMR (300 MHz, CDCl 3 ): 6 0.94-1.04 (s, 3H), 1.20-2.50 (m, 17H), 2.60 2.88 (m, 3H),3.72-3.84 (s, 3H), 4.28-440 (s, 2H), 6.40-6.50 (s, 1H), 6.52-6.60 (d, 1H), 7.04-7.12 (d, 1H),7.14-7.36 (m, 5H). 5 EXAMPLE 156: 1H-NMR (300 MHz, CDCl 3 ): 6 0.96-1.08 (s, 3H), 1.24-2.48 (m, 17H), 2.64 2.88 (m, 3H), 3.72-3.84 (s, 3H), 4.28-4.44 (s, 2H), 6.40-6.50 (s, 1H), 6.50-6.60 (d, 1H), 7.00-7.12 (d, 1H), 7.12-7.36 (m, 5H). EXAMPLES 157 and 158: 10 3-Hydroxy-1 5a-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-(1'-methyl)-pyrazole 3-Hydroxy-1 5a-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-(2'-methyl)-pyrazole /N N-N H O HH H - N I H H N HO HO 0 0 Examples 157 and 158 were prepared according to the procedure described for Examples 155 and 156 using morpholine as amine for the amide coupling step. 15 EXAMPLE 157: 1H-NMR (300 MHz, CDCl 3 ): 6 0.96-1.08 (s, 3H), 1.12-2.36 (m, 17H), 2.72 2.96 (m, 3H), 3.50-3.72 (m, 8H), 3.76-3.86 (s, 3H), 6.44-6.50 (s,1H), 6.52-6.60 (d, 1H), 7.04-7.12 (d, 1 H), 7.24-7.30 (s, 1 H). 20 EXAMPLE 158: 1 H-NMR (300 MHz, CDCl 3 ): 6 0.92-1.08 (s, 3H), 1.24-2.56 (m, 17H), 2.68 2.92 (m, 3H), 3.22-3.70 (m, 8H), 370-3.88 (s, 3H), 6.40-6.48 (s, 1H), 6.48-6.60 (d, 1H), 7.00-7.10 (d, 1H), 7.12-7.22 (s, 1H). EXAMPLES 159 and 160 25 4-(3-Hydroxy-(1 7,16-c)-(1'-methyl)-pyrazolyl-estra-1,3,5(1 0)-trieno-1 5a-yl)-N-(5-methylthiazol-2-yl) butyramide 4-(3-Hydroxy-(1 7,16-c)-(2'-methyl)-pyrazolyl-estra-1,3,5(1 0)-trieno-1 5a-yl)-N-(5-methylthiazol-2-yl) butyramide N N N N H N HH N HO N HO' N 0 O WO 2006/125800 PCT/EP2006/062587 147 Examples 159 and 160 were prepared according to the procedure described for Examples 155 and 156 using 2-amino-5-methylthiazole for the amide coupling step. EXAMPLE 159: 1H-NMR (300 MHz, CDCl 3 ): 6 0.80-0.90 (s, 3H), 0.90-2.48 (m, 20 H), 2.56 5 2.80 (m, 3H), 3.60-3.68 (s, 3H), 6.36-6.42 (s, 1H), 6.44-6.52 (d, 1H), 6.84-6.92 (s,1H), 6.96-7.04 (m, 2H). EXAMPLE 160: 1H-NMR (300 MHz, CDCl 3 ): 6 0.84-0.96 (s, 3H), 0.96-2.48 (m, 20H), 2.58 2.80 (m, 3H), 3.60-3.72 (s, 3H), 6.36-6.44 (s, 1 H), 6.44-6.56 (d, 1 H), 6.84-6.92 (s, 1 H), 6.96-7.04 10 (d, 1H), 7.04-7.08 (s, 1H). EXAMPLE 161: 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-isoxazole H 0 HOH HOO 0 15 Starting from intermediate compound Xc, an allyl side chain was introduced into C15 position using 1,4-addition of allylbromide according to step 1 of SCHEME 7C, followed by construction of the oxazole-ring according to D-(II)-(c) using hydroxylamine for the ringclosure. Conversion of the allyl into the 4-morpholin-4-yl-4-oxo-butyl side chain can be performed according to steps 2 - 4 of SCHEME 7C and to the reaction as depicted in general flow diagram lb by amide coupling with 20 morpholine. EXAMPLE 162: 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-pyrazole H H O | H H N HO 0 25 Starting from intermediate compound Xc, an allyl side chain was introduced into C15 position using 1,4-addition of allylbromide according to step 1 of SCHEME 7C, followed by construction of the pyrazol-ring according to D-(II)-(a) using benzylhydrazine for the ringclosure to give a protected pyrazol. Conversion of the allyl into the 4-morpholin-4-yl-4-oxo-butyl side chain was performed ac cording to steps 2 (metathesis) and 3 (saponification) of SCHEME 7C, followed by amide coupling WO 2006/125800 PCT/EP2006/062587 148 with morpholine according to general flow diagram lb. Finally, reduction of the double bond and debenzylation gave the desired endproduct No. 162. 1H-NMR (300 MHz, CDCl 3 ): 6 1.08-1.20 (s, 3H), 1.22-2.48 (m, 17H), 2.72-3.00 (m, 3H), 3.40 5 3.76 (m, 8H), 6.52-6.56 (s, 1H), 6.56-6.60 (d, 1H), 7.00-7.12 (d, 1H), 7.22-7.28 (s, 1H). IV. Compounds carrying a sulphamate, carbamate, phosphonate, thiophosphonate, sulpho nate, phosphate or sulphate group in RI 10 EXAMPLE 163: 3-Sulphamate-15p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one O H O O0 H NJ H 2N-S0 00 Example 163 was prepared from the Intermediate No. 1 named 3-Hydroxy-15p-(4-morpholin 4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one of formula (Vlp-3a)-1 using sulfamoyl chloride as sul 15 famoylating agent. EXAMPLE 164: 3-Sulphate-15 -(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one 0 H O O | H A ND EtNH+

O-

00 Example 164 was prepared from the Intermediate No. 1 named 3-Hydroxy-15p-(4-morpholin 20 4-yl-4-oxo-butyl)-estra-1,3,5(10)-trien-17-one of formula (Vlp-3a)-1 using sulfur trioxide - triethyl amine complex: The estron derivative (Vlp-3a)-1 (0.25 mmol) and sulfur trioxide - triethylamine complex (54.4 mg, 0.30 mmol, "Fluka") were stirred in anhydrous DMF (1 ml) at RT overnight. Ca. 0.3 g silica gel (for column chromatography) was added, and the solvent was removed in high vac uum at 35 *C. The remaining powder was loaded on the column prepacked with ca. 6 g silica gel. 25 Flash chromatography with afforded the desired triethylammonium phenol sulfate.

WO 2006/125800 PCT/EP2006/062587 149 BIOLOGICAL TESTING MATERIALS AND METHODS 1. Inhibition of the 17p-hydroxysteroid dehydrogenase type 1 enzyme 17p-HSDI purification: Recombinant baculovirus was generated by the "Bac to Bac Ex 5 pression System" (Invitrogen). Recombinant bacmid was transfected to Sf9 insect cells using "Cellfectin Reagent" (Invitrogen). 60h later cells were harvested; the microsomal fraction was iso lated as described by Puranen et al. (1994). Aliquots were stored frozen until determination of en zymatic activity. 10 Assay - Inhibition of recombinant human 17p-hydroxysteroid dehydrogenase type 1: Recombinant protein (0.1pg/ml) was incubated in 20 mM KH 2

PO

4 pH 7.4 with 30 nM 3H-estrone and 1 mM NADPH for 30 min at RT, in the presence of potential inhibitors at concentrations of 1 pM or 0.1 pM. Inhibitor stock solutions were prepared in DMSO. Final concentration of DMSO was adjusted to 1 % in all samples. The enzyme reaction was stopped by addition of 10 % tri 15 chloroacetic acid (final concentration). Samples were centrifuged in a microtiter plate at 4000 rpm for 10 min. Supematants were applied to reverse phase HPLC on a Waters Symmetry C18 column, equipped with a Waters Sentry Guard column. Isocratic HPLC runs were performed at RT at a flow rate of 1 ml/min of acetonitrile:water 48:52 as running solvent. Radioactivity was monitored in the eluate by a Packard Flow Scintillation Analyzer. Total radioactivity for estrone and estradiol were 20 determined in each sample and percent conversion of estrone to estradiol was calculated accord ing to the following formula: % conversion = 100 x {(cpm estradiol in sample with inhibitor) / 25 [(cpm estrone in sample with inhibitor) + (cpm estradiol in sample with inhibitor)]} {(cpm estradiol in sample without inhibitor) / [(cpm estrone in sample without inhibitor) + (cpm estradiol in sample without inhibitor)]}. Percent inhibition was calculated as follows: % inhibition = 100 - %conversion 30 The values "% inhibition" were determined for exemplified compounds, and the results are summarized in Table 19. 35 WO 2006/125800 PCT/EP2006/062587 150 Table 19: Inhibition of 17p-HSD enzyme type I Inhibition of rec. o Compound Structure 171-HSbI 100 nM 1 m 0 CH 2 54.8 74.8 HOH IH H 1N H O 0 H 3 H 19.6 71.2 HHO HO 0 H 0 6 37.9 79.3 30 H H H 398 7. HO 0 0 H 30 H __ 398 736 HO O O H HO /O N3N 68.8 71.9 HO 0 36 H56.9 78.1 0 HO 37 64.0 74.7 H H HO 0 WO 2006/125800 PCT/EP2006/062587 151 Compound SInhibition of rec. o.und Compound Structure 171 - SDl 100 nM 1p m 0 H 38 H H 51.0 76.7 HO0 40 HH N72.0 75. 0 H N 40 H72.0 75.8 N HO 0 0 HOH 0 0 2597F 45 54.0 75.7 HO 0 O H 0O 42 H H 53.3 71.7 HO N0 HO 0O H5 H 55.5 75.0 HO HH H N HO 0 0 H 0 52 H50.0 72.2 1 - H N H HO 0 0 H 55 042.6 71.9 H H ND HO 00 H H H9 0NHN 56.1 69.7 HT-H H H0 WO 2006/125800 PCT/EP2006/062587 152 Compound SInhibition of rec. o.und Compound Structure 171 - SDl 100 nM 1p m 0 H 67 0 42.5 73.2 H H HO HOO 0 0 H 0 71 45.8 70.6 HO H H0 HO

N

H 0 H 78 40.6 72.0 HHHO HOO 0 0 HH H 83 N 53.9 71.6 HOH H H N C HOO 0 F F H 0 90 63.5 81.6 H H NJ HO 0 F F 91 N 32.0 85.0 N HO -<N O F F HH O H3C F F 102 H041.6 70.6

HOH

WO 2006/125800 PCT/EP2006/062587 153 Compound SInhibition of rec. o.und Compound Structure 171 - SDl 100 nM 1 pm F F H 106 36.7 68.0 H H

HO

N H F F H 0 109 NOOH 35.1 70.7 H H N5068. H HO OH IC F F 111 HHN NFN 50.6 68.3 16H H N HO F F 113 N 47.2 76.9 rIH HN HOO

H

3 C F F 116 H 0 49.3 82.4 H H N0 HO

H

3 C F F 120 37.3 85.0 H H N HO H

H

3 C F F H 121 H H N 63.6 92.5 HO 0

H

3 C F F H 122 H 34.0 77.9 H H N0 HO a

H

3 C F 'F H 125 j29.2 76.9 1H H N HO0/ WO 2006/125800 PCT/EP2006/062587 154 Inhibition of rec. C o.und Compound Structure 17 - HSD1 100 nM 1 pm F F H 127 H 21.1 81.3 H O N OH HO 0 OH JHFF 128 N 21.2 71.7 H H N HO 0

H

3 F F H 129 H H H N 33.1 76.9 HO 0 N

H

3 C F F H 131 19.8 71.9 H H N HO O

H

3 C F F H 133 71.4 90.6 H H N HO 0

H

3 C F F H 134 H H N 50.5 88.6 HO 0 OH 161' 21.0 74.0 H H N 0 0 H N N H 0 162 63.0 93.0 H H N HOO 0 WO 2006/125800 PCT/EP2006/062587 155 Compound Inhibition of rec. o.pound Compound Structure 17 -HSD1 100 nM 1p m 0 163 10.0 43.0

H

2 N 0 0 0 -O 164 3.0 27.0 HO 0 0 2. Estrogen Receptor Binding Assay The binding affinity of the compounds of the invention to the estrogen receptor aX and to the estrogen receptor P may be determined according to the in vitro ER binding assays described by 5 Koffman et al (1991). Alternatively, an estrogen receptor binding assay may be performed accord ing to international patent application WO 00/07996. 3. Estrogen Receptor Transactivation Assays 10 Compounds of the invention showing binding affinity towards the estrogen receptor may be further tested with regard to their individual estrogenic or anti-estrogenic potential (agonistic binding or antagonistic binding to the ERax or ERp). The determination of the estrogen receptor agonist ac tivity may be performed according to an in vitro assay system using the MMTV-ERE-LUC reporter system which is for example described within published US patent application US 2003/0170292: 15 To assay estrogen receptor agonist activity, Hela cells are grown in 24-well microtiter plates and then transiently co-transfected with two plasmids using lipofectamine. The first plasmid com prises DNA encoding human estrogen receptor (either ER-alpha or ER-beta), and the second plasmid comprises an estrogen-driven reporter system comprising: a luciferase reporter gene 20 (LUC) whose transcription is under the control of upstream regulatory elements comprising 4 cop ies of the vitellogenin estrogen response element (ERE) cloned into the mouse mammary tumor virus (MMTV) promoter (the full name for the reporter system being "MMTV-ERE-LUC"). Cells are exposed to the compounds of the invention in RPMI 1640 medium, supplemented with 10% char coal-treated fetal calf serum, 2 mM L-glutamine, 0.1 mM non-essential amino acids and 1 mM so 25 dium pyruvate for 42-48 h at 37*C in a 5% carbon dioxide incubator. Concurrently, cells exposed to estradiol (1 nM) serve as positive controls. Replicate wells exposed to the solvent in which the compounds of the invention are dissolved (i.e. ethanol or methanol) are used as negative controls. After the 42-48 h incubation period, cells are rinsed with phosphate buffered saline (PBS), lysis buffer (Promega Corp) is added, and cell lysates are collected for measurement of luciferase activ- WO 2006/125800 PCT/EP2006/062587 156 ity with a luminometer. Estrogenic activity of the compounds of the invention is expressed as fold increase in luciferase activity as compared to that observed in negative control cells. Alternatively, the determination of the estrogen receptor transactivation activity (estrogenicity 5 assay or agonist assay) and of the inhibitory potency of transactivation activity (anti-estrogenicity assay or antagonist assay) may be performed according to international patent application WO 00/07996. 4. STS ASSAY - INHIBITION OF STEROID SULPHATASE ACTIVITY IN MCF-7 CELLS 10 Steroid sulphate activity is measured in vitro using intact MCF-7 human breast cancer cells. This hormone dependent cell line is widely used to study the control of human breast cancer cell growth. It possesses significant steroid sulphate activity and is available in the U.S.A. form the American Type Culture Collection (ATCC) and in the U.K. (e.g. from The Imperial Cancer Research 15 Fund). Cells are maintained in Minimal Essential Medium (MEM) (Flow Laboratories, Irvine, Scot land) containing 20 mM HEPES, 5% foetal bovine serum, 2 mM glutamin, non-essential amino ac ids and 0.075% sodium bicarbonate. Up to 30 replicate 25 cm2 tissue culture flasks are seeded 20 with approximately 1 x 105 cells/flask using the above medium. Cells are grown to 80% confluency and the medium is changed every third day. Intact monolayers of MCF-7 cells in triplicate 25 cm2 tissue culture flasks are washed with Earle's Balanced Salt Solution (EBSS from ICN Flow, High Wycombe, U.K.) and incubated for 3-4 25 h at 37*C with 5 pmol (7 x 105 dpm) [6,7- 3 H] oestrone-3-sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) in serum-free MEM (2.5 ml) together with oestrone 3-sulphamate (11 concentrations: 0; 1fM; 0.O1pM; 0.1pM; 1pM; 0.01nM; 0.1nM; 1nM; 0.01mM; 0.1mM; 1mM). After incubation each flask is cooled and the medium (1ml) is pipette into separate tubes containing [14C] oestrone (7 x 103 dpm) (specific activity 97 Ci/mmol from Amersham Interna 30 tional Radiochemical Centre, Amersham, U.K.). The mixture is shaken thoroughly for 30 seconds with toluene (5 ml). Experiments have shown that >90% [ 1 4 C] oestrone and <0.1% [ 3 H] oestrone-3 sulphate is removed from the aqueous phase by this treatment. A portion (2ml) of the organic phase is removed, evaporated and the 3 H and 1 4 C content of the residue determined by scintillation spectrometry. The mass of oestrone-3-sulphate hydrolyse was calculated from the 3 H counts ob 35 tained (corrected for the volumes of the medium and organic phase used, and for recovery of [14C] oestrone added) and the specific activity of the substrate. Each batch of experiments includes in cubations of microsomes prepared from a sulphatase-positive human placenta (positive control) and flasks without cells (to assess apparent non-enzymatic hydrolysis of the substrate). The num ber of cell nuclei per flask is determined using a Coulter Counter after treating the cell monolayers WO 2006/125800 PCT/EP2006/062587 157 with Zaponin. One flask in each batch is used to assess cell membrane status and viability using the Trypan Blue exclusion method. Results for steroid sulphate activity are expressed as the mean ± 1 S.D. of the total product 5 (oestrone + oestradiol) formed during the incubation period (20 h) calculated for 106 cells and, for values showing statistical significance, as a percentage reduction (inhibition) over incubations con taining no oestrone-3-sulphamate. Unpaired Student's t-test was used to test the statistical signifi cance of resutts. 10 5. CHO/STS ASSAY CHO cells stably transfected with human steroid sulfatase (CHO/STS) are seeded into mi crotiter plates. After reaching approximately 90% confluency, they are incubated overnight with graded concentrations of test substances (e. g. compounds of the present invention or compounds 15 for use in the present invention). They are then fixed with 4% paraformaldehyde for 10 min at RT and washed 4 times with PBS, before incubation with 100 pl/well 0.5mM 4-methylumbelliferyl sul fate (MUS), dissolved in 0.1 M Tris-HCI, pH 7.5. The enzyme reaction is carried out at 37*C for 30 min. Then 50pl/well stop solution (1 M Tris-HCI, pH 10.4) are added. The enzyme reaction solutions are transferred to white plates (Microfluor, Dynex, Chantilly, VA) and read in a Fluoroskan 11 or 20 Tecan fluorescence microtiter plate reader. Reagent blanks are subtracted from all values. Option ally, for drug testing, the fluorescence units (FU) can be divided by the optical density readings af ter staining cellular protein with sulforhodamine B (OD 5 5 0 ), in order to correct for variations in cell number. IC 50 values are determined by linear interpolation between two bracketing points. In each assay with inhibitors, estrone 3-0-sulfamate is run as a reference compound, and the IC50 values 25 are normalized to estrone 3-0-sulfamate (relative IC 50 = IC 50 compound/IC 50 estrone 3-0 sulfamate). 6. STS INHIBITION IN PLACENTA MICROSOMES 30 Sulphatase-positive human placenta from normal term pregnancies are thoroughly minced with scissors and washed once with cold phosphate buffer (pH 7.4, 50 mM) then re-suspended in cold phosphate buffer (5 ml/g tissue). Homogenisation is accomplished with an Ultra-Turrax ho mogeniser, using three 10 second bursts separated by 2 min cooling periods in ice. Nuclei and cell debris are removed by centrifuging (4*C) at 2000g for 30 min and portions (2 ml) of the supernatant 35 are stored at 20*C. The protein concentration of the supernatants is determined by the method of Bradford [Anal. Biochem. 72:248-254 (1976)]. Incubations (1 ml) are carried out using a protein concentration of 100 mg/ml, substrate con centration of 20 mM [6,7- 3 H] oestrone-3-sulphate (specific activity 60 Ci/mmol from New England WO 2006/125800 PCT/EP2006/062587 158 Nuclear, Boston, Mass., U.S.A.) and an incubation time of 20 min at 37 0 C. If necessary eight con centrations of compounds are employed: 0 (i.e. control); 0.05mM; 0.1mM; 0.2mM; 0.4mM; 0.6mM; 0.8mM; and 1.0mM. After incubation each sample is cooled and the medium (1 ml) was pipetted into separate tubes containing [14C] oestrone (7 x 103 dpm) (specific activity 97 Ci/mmol from Am 5 ersham International Radiochemical Centre, Amersham, U.K.). The mixture is shaken thoroughly for 30 seconds with toluene (5 ml). Experiments have shown that >90% [14C] oestrone and <0.1% [3H] oestrone-3-sulphate is removed from the aqueous phase by this treatment. A portion (2 ml) of the organic phase was removed, evaporated and the 3 H and 14C content 10 of the residue determined by scintillation spectrometry. The mass of estrone-3-sulphate hydrolyse is calculated from the 3 H counts obtained (corrected for the volumes of the medium and organic phase used, and for recovery of [14C] oestrone added) and the specific activity of the substrate. 7. ANIMAL ASSAY MODEL FOR DETERMINING STS ACTIVITY 15 The inhibition of STS activity in vivo may be determined by using the compounds of the pre sent invention in an animal model, in particular in ovariectomised rats. In this model compounds which are estrogenic stimulate uterine growth. The compound (10 mg/Kg/day for five days) was administered orally to rats with another group of animals receiving vehicle only (propylene glycol). 20 A further group received the compound EMATE subcutaneously in an amount of 10 pg/day for five days. 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Biol., 66:179-191 25 * US 2003/0170292 * US 3,275,623 e US 3,347,878 * US 3,413,321 e US 6,043,236 30 e Verdier-Pinard et al (2000) "A steroid derivative with paclitaxel-like effects on tubulin polym erization." Mol Pharmacol. 57(3):568-75. * Wang & Ruan (1994) "Trifluoromethylation of steroidal ketones" J. Fluorine Chem. 69(1):1-3 e WO 93/05063 e WO 96/15257 35 e WO 96/28462 e WO 00/07996 e WO 02/32409 e WO 03/017973 WO 2006/125800 PCT/EP2006/062587 161 e WO 2004/080271 e WO 2004/085345 e WO 2004/085457 e WO 2004/085459 5 e WO 2005/047303 e WO 2006/003012 (also published as US2006052461) e WO 2006/003013 (also published as US2006009434) e WO 2006/027347 e W61fling et al (2003) ,,Synthesis and receptor-binding examinations of the normal and 13-epi 10 D-homoestrones and their 3-methyl ethers" Steroids 68:277-288 e Xenos & Catsoulacos (1985) ,,Synthesis of 16,17-pyrazolo-fused derivatives of A-homo steroidal ring A lactams" Synthesis 3:307-9 e Yoshikawa et al. (2002) "Diastereo- and Enantioselective Direct Catalytic Aldol Reaction of 2-Hydroxyacetophenones with Aldehydes Promoted by a Heteropolymetallic Complex: Cata 15 lytic Asymmetric Synthesis of anti- 1,2-Diols" J. Org. Chem. 67(8); 2556-2565.

Claims (37)

1. A compound of the general formula 1, R13 R12 R11 R14 H Rio (I) O y1 A 'Y"R2 5 wherein -X-A-Y- together represent a group selected from (a) -CO-NR 4 -, (b) -CO-O-, (c) -CO-, (d) -CO-NH-NR 4 -, 10 (e) -NH-CO-NH-, (f) -NH-CO-0-, (g) -NH-CO-, (h) -NH-CO-NH-SO 2 -, (i) -NH-SO

2- NH-, 15 (j) -NH-SO 2- O-, (k) -NH-SO 2 (1) -0-CO-NH-, (m) -O-CO-, (n) -O-CO-NH-SO 2- NR 4 -, and 20 (o) -0-; n represents 1, 2, 3, 4, 5 or 6, or, if -X-A-Y- represents -CO-NR 4 -, -CO-O-, -CO-, or -CO NH-NR 4 -, then n may also represent 0; 25 R 1 is selected from: (a) -H, (b) -(C1-C 6 )alkyl, which is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , or -COOR 6 ; the number of said substituents being 1, 2 or 3 for halogen, and 1 or 2 for any combina tion of said halogen, nitril, -OR 6 , -SR 6 , or -COOR 6 moieties, 30 (c) -phenyl, which is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , -R 6 , or -COOR 6 , the number of said substituents being up to perhalo for halogen, and 1 or 2 for any com bination of said halogen, nitril, -OR 6 , -SR 6 , -R 6 or -COOR 6 moieties, WO 2006/125800 PCT/EP2006/062587 163 (d) -(C1-C 4 )alkyl-phenyl, in which the alkyl portion is optionally substituted with up to three halogens; and the phenyl portion is optionally substituted with halogen, nitril, -OR 6 , -SR 6 , -R or -COOR , the number of substituents on said phenyl portion being up to perhalo for halogen, and 1 or 2 for any combination of said halogen, nitril, -OR , -SR 6 , -R 6 or 5 COOR 6 moieties, (e) -SO 2 -NR

3 R 3 , (f) -CO-NR 3 R 3 , (g) -PO(OR )-R 3 , (h) -PS(OR )-R 3 , 10 (i) -PO(OR 6 )-O-R 3 (j) -S0 2 -R 3 , and (k) -S0 2 -0-R 3 ; wherein 15 R 6 represents H, -(C1-C 4 )alkyl or halogenated -(C1-C 4 )alkyl; R 3 and R 3 ' are independently selected from H, alkyl, aryl and arylalkyl, or R 3 and R3' form to gether with the nitrogen atom, to which R 3 and R3' are attached, a heterocyclic 4-, 5-, 6-, 7 or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, 0 and S, the number 20 of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; and R 1 6 represents -H, alkyl, or arylalkyl; R2 and R4 are independently selected from: 25 (a) -H, (b) optionally substituted alkyl, (c) optionally substituted acyl, under the proviso that -X-A-Y- represent -CO-NH-NR 4 -, (d) optionally substituted aryl, (e) optionally substituted heteroaryl, and 30 (f) optionally substituted cycloheteroalkyl, or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a heterocyclic

4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated, partly unsaturated, or aromatic; which optionally contains up to three additional heteroatoms selected from N, 0 and S, the 35 number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or the ring-system is optionally substituted; WO 2006/125800 PCT/EP2006/062587 164 the substituents Rio, R", R 1 2 and R 1 3 together with the carbon atoms, to which they are attached, form a structure R13 R1 11 which is selected from the group of 2 CF F CHF F F CF 3 CHF 2 F CF 3 and 5 or, the substituents Rio, R", R 1 2 and R 1 3 together with the carbon atoms, to which they are at tached, form a heterocyclic 5- or 6-membered ring, which is partly unsaturated or aromatic, which contains one, two or three heteroatoms independently selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, 10 wherein one heteroatom is directly attached to the C1 7 C-atom of the steroidal core; and which ring is optionally substituted with an alkyl group; R 1 represents an alkyl, alkoxy, or alkoxy-alkyl group, or R 1 may also represent -H, under the proviso that at least 15 (i) R 1 represents -SO 2 -NR 3 R 3 ', -CO-NR 3 R 3 ', -PO(OR 6 )-R 3 , -PS(OR 6 )-R 3 , -PO(OR 16 ) OR 3 , -S0 2 -R 3 , or -S0 2 -OR 3 ; or (ii) R13 O R is different from and all pharmacologically acceptable salts thereof. 20 2. A compound according to claim 1, wherein R2 and R4 are independently selected from: (a) -H, wherein, if -X-A-Y- together represents -CO-0- or -CO-, then R2 is different from -H, 25 (b) -(C1-C 1 2 )alkyl, optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, thiol, nitrile, alkoxy, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyl, acylamino, WO 2006/125800 PCT/EP2006/062587 165 aryl, which aryl is optionally substituted with up to three substituents independently se lected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-C)alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylthio, aryl 5 thio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 10 and S atoms each being being 0, 1 or 2; heteroaryl, which heteroaryl is optionally substituted with up to three substituents inde pendently selected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-C 6 )alkyl, halogenated (C1-C 6 )alkoxy, carboxyl-(C1 C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1 15 C 6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino, aryl-(C1-C 4 )-alkyl and aryl; whereby each aryl group is optionally substituted with up to three substituents in dependently selected from the group consisting of hydroxyl, halogen, (C1 C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-C 6 )alkyl and halogenated (C1 20 C 6 )alkoxy; and cycloheteroalkyl, which cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C1-C 8 )-alkyl, aryl, aryl-(C1-C 4 )-alkyl, hydroxyl, (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylthio, arylthio, 25 arylalkylthio, amino, amido, acyl, and acylamino, whereby each aryl group is optionally substituted with up to three substituents in dependently selected from the group consisting of hydroxyl, halogen, (C1 C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, and halogenated (C1 C 4 )-alkoxy); 30 (c) acyl -(C=O)-R', wherein R' represents hydrogen, (C1-C 4 )alkyl, aryl, or aryl-(C1-C 4 )alkyl, or heteroaryl-(C1-C 4 )alkyl; which aryl or aryl-(C1-C 4 )alkyl is optionally substituted in the aryl moiety with up to three substituents independently selected from the group consisting of hydroxyl, halo gen, (C 1 -C 4 )alkoxy, (C 1 -C 4 )-alkyl or halogenated (C 1 -C 4 )alkyl; 35 (d) aryl which aryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, halo genated (C 1 -C 6 )alkyl, halogenated (C 1 -C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, nitro, sulfamoyl, sulfonamide, carboxyl, aryloxy, arylalkyloxy, (C 1 -C 6 )alkylsulfonyl, WO 2006/125800 PCT/EP2006/062587 166 arylsulfonyl, (C1-C 6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or which aryl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 5 membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or2; (e) heteroaryl, which heteroaryl is optionally substituted with up to three substituents independently se 10 lected from the group consisting of halogen, hydroxyl, (C1-C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-Ce)alkyl, halogenated (C1-Ce)alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, arylsulfoxy, carboxyl, aryloxy, arylalkyloxy, (C1 C 6 )alkylsulfonyl, arylsulfonyl, (C1-C 6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, acylamino, aryl-(C1-C 4 )-alkyl and aryl, 15 whereby each aryl group is optionally substituted with up to three substituents in dependently selected from the group consisting of hydroxyl, halogen, (C1 C 6 )alkoxy, (C1-C)alkyl, halogenated (C1-C 6 )alkyl and halogenated (C1 C 6 )alkoxy; or (f) cycloheteroalkyl, 20 which cycloheteroalkyl is optionally substituted with up to three substituents independ ently selected from the group consisting of oxo, (C1-C 14 )-alkyl, aryl, aryl-(C1-C 4 ) alkyl, hydroxyl, (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, thiol, nitrile, sulfamoyl, sul fonamide, carboxyl, aryloxy, arylalkyloxy, (C1-C 6 )alkylthio, arylthio, arylalkylthio, amino, amido, acyl, and acylamino, 25 whereby each aryl group is optionally further substituted with up to three substitu ents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, and halogenated (C1-C 4 )-alkoxy; or wherein R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a het 30 erocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is optionally saturated or partly unsaturated; which optionally contains up to three additional heteroatoms selected from N, 0 and S, the number of additional N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, wherein the ring or the ring-system is optionally substituted 35 (i) with up to three substituents independently selected from the group consisting of (C 1 -C 8 ) alkyl, halogen, hydroxyl, carboxyl, thiol, nitrile, (C1-C)-alkoxy, carboxyl-(C1-C 6 )alkyl, ary loxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, aryl, aryl-(C1-C 4 )-alkyl, heteroaryl, and cycloheteroalkyl, WO 2006/125800 PCT/EP2006/062587 167 wherein the (C1-C 8 )-alkyl group is optionally substituted with up to three substituents in dependently selected among hydroxyl, halogen, (C1-C 4 )-alkoxy, or halogenated (C1-C 4 )-alkoxy, whereby the alkyl-chain of the (C1-C 4 )-alkoxy moiety is optionally substituted with 5 hydroxyl; wherein the aryl group or aryl moiety is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C 1 -C 4 ) alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, halogenated (C1-C 4 )-alkoxy and carboxyl-(C1-C 6 )alkyl, or wherein the aryl moiety is optionally substituted by two 10 groups which are attached to adjacent carbon atoms and are combined into a satu rated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N at oms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2; wherein the heteroaryl group is optionally substituted with up to three substituents inde 15 pendently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, halogenated (C1-C 4 )-alkoxy) and car boxyl-(C1-C 6 )alkyl; wherein the cycloheteroalkyl is optionally substituted with up to three substituents inde pendently selected from the group consisting of oxo, (C1-C 8 )-alkyl, aryl, aryl-(C1 20 C 4 )-alkyl, hydroxyl, (C1-C 6 )alkoxy, carboxyl-(C1-C 6 )alkyl, and carboxyl, whereby each aryl group is optionally further substituted with up to three substitu ents independently selected from the group consisting of hydroxyl, halogen, (C1-C 4 )-alkyl, (C1-C 4 )-alkoxy, halogenated (C1-C 4 )-alkyl, and halogenated (C1-C 4 )-alkoxy); or 25 (ii) by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8-membered ring system, optionally containing up to three heteroatoms selected from N, 0 and S, the number of N atoms be ing 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, whereby the cyclic ring system is optionally substituted by up to two substituents inde 30 pendently selected from oxo, (C1-C)-alkyl, aryl and aryl-(C1-C 4 )-alkyl; and wherein n represents (a) 1, 2, 3, 4, 5 or 6, if -X-A-Y- together represent -NH-CO-NR 4 -, -NH-CO-0-, -NH CO-, -NH-CO-NH-SO 2 -, -NH-SO 2 -NR 4 -, -NH-SO - O-, -NH-SO 2- , -O-CO-NR 4 - 35 O-CO-, -O-CO-NH-SO 2 -NR 4 -, or -0-, or (b) 0, 1, 2, 3, 4, or 5, if -X-A-Y- together represent -CO-NR 4 -, -CO-O-, -CO-, or -CO NH-NR 4 -. WO 2006/125800 PCT/EP2006/062587 168 3. A compound of the general formula I according to claim 1 or 2, which is an optically pure enantiomer having the formula (II) R13 R12 H H R R)n O, A 'Y"R2 or a physiologically acceptable salt thereof. 5 4. A compound of the general formula I according to claims 1 or 2, which is an optically pure enantiomer having the formula (111) R13 R12 R1R11 R14 H R10(1) R1 H H ) O y A 'Y",R2 or a physiologically acceptable salt thereof. 10

5. A compound according to any of the preceding claims 1 to 4, wherein R 1 is selected from: (a) -SO 2 -NR 3 R 3 , (b) -CO-NR 3 R 3 , 15 (c) -PO(OR1 6 )-R 3 , (d) -PS(OR1 6 )-R 3 , (e) -PO(OR1 6 )-O-R 3 , (f) -S02-R3; and (g) -S02-0-R3; 20 wherein R 3 and R 3 ' are independently selected from -H, -(C1-C 8 )alkyl, phenyl and -(C1-C 4 )alkyl phenyl, or R 3 and R 3 ' together with the nitrogen atom, to which R 3 and R3' are attached, form a het erocyclic 4-, 5-, 6-, 7- or 8-memberred ring, which is selected from the group consist 25 ing of WO 2006/125800 PCT/EP2006/062587 169 -N -N 0 -N S -N N -N -N -N -N -No and -N\) R 16 represents -H, -(C1-C 4 )alkyl, or -(C1-C 4 )alkyl-phenyl, R 1 0 and R 1 1 both represent -H and R 12 and R 13 together represent =0; and R 4 represents -H, -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C1-C 8 )alkyl-O-(C1-C)alkyl. 5

6. A compound according to claim 5, wherein R 1 represents -SO 2 -NR 3 R 3 ', wherein R 3 and R 3 together with the nitrogen atom, to which R 3 and R 3 are attached, form a heterocyclic ring, which is selected from the group consisting of morpholine, thiomorpholine and piperazyl, or wherein R 1 represents -SO 2 -NH 2 , and 10 R 4 represents -H.

7. A compound according to any of the preceding claims 1 to 4, wherein R 1 represents -H, (C1-C 4 )alkyl, or -(C1-C 4 )alkyl-phenyl; and R 1 0 and R 1 1 both represent -H and R 12 and R 1 3 together represent =0; and 15 R 4 represents -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C1-C 8 )alkyl-O-(C1-C)alkyl.

8. A compound according to claim 7, wherein R 4 represents -(C1-C 4 )alkyl, -O-(C1-C 4 )alkyl, or -(C1-C 4 )alkyl-O-(C1-C 4 )alkyl. 20

9. A compound according to claim 8, wherein R 1 represents -H, and R 4 represents ethyl, propyl, methoxyethyl, methoxy, ethoxy or methoxyethoxy.

10. A compound according to any of the preceding claims 1 to 4, wherein 25 R 1 represents -H, (C1-C 4 )alkyl, or -(C1-C 4 )alkyl-phenyl; the substituents Rio, R", R 12 and R 13 together with the carbon atoms, to which they are at tached, form a structure R13 R1 11 R1o which is selected from the group of WO 2006/125800 PCT/EP2006/062587 170 CF 2 F CHF 2 F F CF 3 CHF 2 F CF 3 and ,and R 1 represents -H, -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C1-C 8 )alkyl-O-(C1-C)alkyl.

11. A compound according to claim 10, wherein 5 the substituents Rio, R", R 12 and R 13 together with the carbon atoms, to which they are at tached, form a structure R13 R 1 Rio which is selected from the group of F CF 2 F CF 3 F and 10

12. A compound according to claim 11, wherein R and R each individually represent -H.

13. A compound according to any of the preceding claims 1 to 4, wherein R 1 represents -H, (C1-C 4 )alkyl, or -(C1-C 4 )alkyl-phenyl; the substituents Rio, R", R and R 1 3 together with the carbon atoms, to which Rio, R", R1 15 and R 13 are attached, form a heterocyclic 5- or 6-membered ring, which is partly unsatu rated or aromatic, which contains one, two or three heteroatoms independently selected from N, 0 and S, the number of N atoms being 0, 1, 2 or 3 and the number of 0 and S atoms each being 0, 1 or 2, wherein one heteroatom is directly attached to the C17 C atom of the steroidal core; and which ring is optionally substituted with an alkyl group; 20 and R 1 represents -H, -(C1-C 8 )alkyl, -O-(C1-C)alkyl, or -(C1-C 8 )alkyl-O-(C1-C)alkyl.

14. A compound according to claim 12, wherein the substituents Rio, R", R and R 13 together with the carbon atoms, to which Rio, R", R1 25 and R 13 are attached, form a heterocyclic 5- or 6-membered ring to provide a com pound of one of the following formulas WO 2006/125800 PCT/EP2006/062587 171 R15 N NN R1R14 H 0A R2 A R 2 O- N O_ R14 H R4 H K 0H H KH H 0 X. A YR 2 O XsA NR2 , orA wherein R 1 5 represents -H or -(C1-C 4 )alkyl. 5

15. A compound according to claim 14, wherein R and R each individually represent -H.

16. A compound according to any of the preceding claims 1 to 4, wherein R 1 represents -H or -SO 2 -N H 2 , 10 the substituents Rio, R", R 12 and R 13 together with the carbon atoms, to which they are at tached, form a structure R 1 3 R 1 2 11 , which is selected from the group of 0 F CF 2 F CF 3 H F N andN ;and R 4 represents -H, -(C1-C 4 )alkyl, -O-(C1-C 4 )alkyl, or -(C1-C 4 )alkyl-O-(C1-C 4 )alkyl. 15

17. A compound according to any of the preceding claims 1 to 16, wherein -X-A-Y- together represent a group selected from -CO-NR 4 -, -CO-O-, -CO-, and -CO-NH-NR 4 -; and n represents 0, 1, 2, 3, 4, or 5. 20

18. A compound according to claim 17, wherein -X-A-Y- together represent -CO-NR 4 -.

19. A compound according to claim 18, wherein n represents 2, 3 or 4.

20. A compound according to claim 18 or 19, wherein WO 2006/125800 PCT/EP2006/062587 172 R 2 represents (i) -(C1-C 4 )alkyl, which is optionally substituted with one or two substituents independ ently selected from the group consisting of hydroxyl, halogen, and (C1-C 4 )alkoxy; (ii) -(C 3 -C 8 )cycloalkyl; 5 (iii) aryl or -(C1-C 4 )alkyl-aryl, wherein the aryl is phenyl or naphthyl, which phenyl is optionally substituted with one or two substituents independently se lected from the group consisting of hydroxyl, halogen, cyano, (C1-C 4 )alkoxy and halogenated (C1-C 4 )alkoxy; or which phenyl is optionally substituted by two groups which are attached to adjacent 10 carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 0 atoms; or (iv) heteroaryl or -(C1-C 4 )alkyl-heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, indazolyl, or benzoimidazolyl; which heteroaryl is optionally substituted with one or two substituents independently 15 selected from the group consisting of -(C1-C 4 )alkyl and -(C1-C 4 )alkyl-(C=O) O-(C1-C 4 )alkyl; and R 4 is independently selected from H or -(C1-C 4 )-alkyl or -(C1-C 4 )-alkyl-phenyl, wherein the phenyl group is optionally substituted with one or two (C1-C 4 )alkoxy groups; or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a ring or 20 ringsystem, which is selected from the group consisting of morpholine, piperidine, thio morpholine and piperazine, wherein the ring or the ring-system is optionally substituted with a -(C1-C 4 )alkyl group.

21. A compound according to claim 20, wherein 25 R 2 represents (i) -(C1-C 4 )alkyl, which is optionally substituted with one or two (C1-C 4 )alkoxy groups; (ii) -(C 3 -C 8 )cycloalkyl; (iii) phenyl or -(C1-C 4 )alkyl-phenyl, which phenyl is optionally substituted with one or two substituents independently se 30 lected from the group consisting of hydroxyl, halogen, cyano and (C1-C 4 )alkoxy; or which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 0 atoms; or 35 (iv) heteroaryl or -(C1-C 4 )alkyl-heteroaryl, wherein the heteroaryl is thiazolyl, pyridinyl, in dolyl, or indazolyl; which heteroaryl is optionally substituted with one or two -(C1-C 4 )alkyl groups; and R 4 is independently selected from -H, -(C1-C 4 )-alkyl or -(C1-C 4 )-alkyl-phenyl, wherein the phenyl group is optionally substituted with one or two (C1-C 4 )alkoxy groups; or WO 2006/125800 PCT/EP2006/062587 173 R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a ring, which is selected from the group consisting of morpholine, piperidine, and piperazine, wherein the ring is optionally substituted with a -(C1-C 4 )alkyl group. 5

22. A compound according to claim 18, wherein R 2 represents a -(C1-C 4 )alkyl-phenyl or a thiazolyl group, optionally substituted with -(C 1 C 4 )-alkyl, and R 4 represents -H; or R2 and R4 form together with the nitrogen atom, to which R2 and R4 are attached, a mor pholinyl group, and 10 n represents 2 or 3.

23. A compound according to claim 1, selected from the group consisting of exemplary com pounds: N-Benzyl-4-(2-ethyl-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide 15 N-Benzyl-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide N-Benzyl-4-(3-hydroxy-2-(2-methoxy-ethyl)-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide N-Benzyl-4-(3-hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-butyramide 2-Ethyl-3-hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-2-propyl-estra-1,3,5(1 0)-trien-1 7-one 20 3-Hydroxy-2-(2-methoxy-ethyl)-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7 one 3-Hydroxy-2-methoxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one 4-(2-Ethyl-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl) butyramide 25 4-(3-Hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl) butyramide N-Benzo[1,3]dioxol-5-ylmethyl-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl) butyramide 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-pyridin-3-ylmethyl-butyramide 30 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-[2-(7-methyl-1 H-indol-3-yl) ethyl]-butyramide 3-Hydroxy-1 5p-(4-oxo-4-piperidin-1 -yl-butyl)-2-propyl-estra-1,3,5(1 0)-trien-1 7-one N-Benzyl-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-methyl-butyramide N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p 35 yl)-N-methyl-butyramide 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(1 H-indazol-6-yl)-butyramide 4-(3-Hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(2-methoxy-ethyl)-butyramide WO 2006/125800 PCT/EP2006/062587 174 N-(2,4-Difluoro-benzyl)-4-(3-hydroxy-1 7-oxo-2-propyl-estra-1,3,5(1 0)-trien-1 5p-yl) butyramide N-Cyclohexyl-4-(2-ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide N-Benzo[1,3]dioxol-5-ylmethyl-4-(2-ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl) 5 butyramide 4-(2-Ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-N-[2-(7-methyl-1 H-indol-3-yl) ethyl]-butyramide 2-Ethoxy-3-hydroxy-1 5a-(4-oxo-4-piperidin-1 -yl-butyl)-estra-1,3,5(1 0)-trien-1 7-one 4-(2-Ethoxy-3-hydroxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-N-(1 H-indazol-6-yl)-butyramide 10 N-Cyclohexyl-4-(3-hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide N-Benzyl-4-(3-hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yi)-butyramide 3-Hydroxy-2-methoxy-1 5a-(4-oxo-4-piperidin-1 -yl-butyl)-estra-1,3,5(1 0)-trien-1 7-one 4-(3-Hydroxy-2-methoxy-1 7-oxo-estra-1,3,5(1 0)-trien-1 5a-yl)-N-(1 H-indazol-6-yl)-butyramide 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-1 -morpholin-4-yl-butan-1 -one 15 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -morpholin-4-yl-butan-1 -one 4-(17-Fluoro-3-hydroxy-estra-1,3,5(10),16-tetraen-1 5p-yl)-l -morpholin-4-yl-butan-1 -one 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(5-methyl-thiazol-2-yl) propionamide 4-(17-Difluoromethylene-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -morpholin-4-yl-butan-1 20 one N-Cyclohexyl-4-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide N-Benzyl-4-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-butyramide 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-N-(3,4-dihydroxy-benzyl) butyramide 25 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyl] butyramide 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-1 -piperidin-1 -yl-butan-1 -one 4-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5a-yl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl] N-methyl-butyramide 30 N-Cyclopropyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propionamide N-Cyclohexyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propionamide N-Benzo[1,3]dioxol-5-ylmethyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl) propionamide N-Benzyl-3-(17,17-difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-propionamide 35 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(3,4-dihydroxy-benzyl) propionamide 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-(3,5-dimethoxy-benzyl) propionamide WO 2006/125800 PCT/EP2006/062587 175 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-[2-(7-methyl-1 H-indol-3-yl)-ethyl] propionamide 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-l -piperidin-1 -yl-propan-1 -one 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N, N-diethyl-propionamide 5 3-(17,17-Difluoro-3-hydroxy-estra-1,3,5(1 0)-trien-1 5p-yl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl] N-methyl-propionamide 3-Hydroxy-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-[1 6,17-c]-pyrazole 3-Sulphamate-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one, 3-Sulphate-1 5p-(4-morpholin-4-yl-4-oxo-butyl)-estra-1,3,5(1 0)-trien-1 7-one, 10 and any physiologically acceptable salt thereof.

24. A compound according to any of the claims 1 to 23, for use as a medicament.

25. A pharmaceutical composition comprising as active agent a compound of formula (1) accord 15 ing to any of the claims 1 to 23, and at least one pharmaceutically acceptable carrier.

26. Use of an effective amount of a compound of formula (1) according to any of the preceding claims 1 to 23 for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal. 20

27. Use of a compound of formula (1) according to any of the preceding claims 1 to 23 for the manufacture of a medicament for the treatment or prevention of a steroid hormone depend ent disease or disorder in a mammal. 25

28. Use of a compound of formula (1) according to claim 26 or 27, wherein the steroid hormone dependent disease or disorder is an estradiol dependent disease or disorder.

29. Use of a compound of formula (1) according to claim 28, wherein the estradiol dependent disease or disorder is malign and is selected from the group consisting of breast cancer, 30 ovarian cancer, uterine cancer, endometrial cancer, and endometrial hyperplasia.

30. Use of a compound of formula (1) according to claim 29, wherein the malign disease or dis order is characterized by a detectable level of 17p-HSD1 and/or STS expression within a cancer tissue sample. 35

31. Use of a compound of formula (1) according to claim 29 or 30, wherein the estradiol depend ent disease is breast cancer and the mammal is a human post-menopausal female. WO 2006/125800 PCT/EP2006/062587 176

32. Use of a compound of formula (1) according to claim 31, wherein the estradiol dependent disease or disorder is benign and is selected from the group consisting of endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metror rhagia, and urinary dysfunction. 5

33. Use of a compound of formula (1) according to any of the claims 29, 30 or 31, wherein the mammal is a human pre- or peri-menopausal female.

34. Use of a compound of formula (1) according to claim 26 or 27, wherein steroid hormone de 10 pendent disease or disorder is an androgen-dependent disease or disorder.

35. Use of a compound of formula (1) according to claim 34, wherein the androgen-dependent disease or disorder is selected from the group consisting of acne, seborrhea, androgenetic alopecia, hirsutism, and prostate cancer. 15

36. Use of a compound of formula (1) according to claim 26 or 27, wherein the steroid hormone dependent disease or disorder is an estrogen- or androgen dependent disease or disorder requiring the lowering of the endogeneous estrogen or androgen concentration in a general ized or tissue-specific manner. 20

37. Use of a compound of formula (1) according to claim 36, wherein the disease or disorder is selected from the group consisting of prostadynia, benign prostatic hyperplasia, urinary dys function, lower urinary tract syndrome, squamous cell carcinoma, rheumatoid arthritis, type I and 11 diabetes, systemic lupus erythematosus, multiple sclerosis, myastenia gravis, thyroidi 25 tis, vasculitis, ulcerative colitis, Crohn's disease, psoriasis, contact dermatitis, graft versus host disease, eczema, asthma, organ rejection following transplantation, colon cancer, tissue wounds, skin wrinkles, cataracts, cognitive dysfunctions, senile dementia and Alzheimer's disease.